Heritability of autism 3232713 226074279 2008-07-16T18:39:14Z Eubulides 3573537 Add PMID for Morrow et al. 2008, now that the PMID is published. Genetic factors are the most significant cause for [[autism]] spectrum disorders. Early studies of twins estimated the '''heritability of autism''' to be more than 90%; in other words, that genetics explains more than 90% of autism cases.<ref name=Freitag/> This may be an overestimate; new twin data and models with structural genetic variation are needed.<ref name=Sykes/> When only one identical twin is autistic, the other often has learning or social disabilities. For adult siblings, the risk of having one or more features of the broader autism phenotype might be as high as 30%,<ref name=Folstein>{{cite journal |author= Folstein SE, Rosen-Sheidley B |title= Genetics of autism: complex aetiology for a heterogeneous disorder |journal= Nat Rev Genet |date=2001 |volume=2 |issue=12 |pages=943–55 |doi=10.1038/35103559 |pmid=11733747}}</ref> much higher than the risk in controls.<ref name=Bolton/> The genetics of autism is complex.<ref name=Freitag/> [[Genetic linkage]] analysis has been inconclusive; many [[Genetic association|association analyses]] have had inadequate power.<ref name=Sykes>{{cite journal |journal= Expert Rev Mol Med |year=2007 |volume=9 |issue=24 |pages=1–15 |title= Autism: the quest for the genes |author= Sykes NH, Lamb JA |pmid=17764594 |doi=10.1017/S1462399407000452}}</ref> For each autistic individual, [[mutation]]s in more than one gene may be implicated. Mutations in different sets of genes may be involved in different autistic individuals. There may be significant interactions among mutations in several genes, or between the environment and mutated genes. By identifying genetic markers inherited with autism in family studies, numerous candidate genes have been located, most of which encode proteins involved in [[neural development]] and function.<ref>{{cite journal |author= Persico AM, Bourgeron T |title= Searching for ways out of the autism maze: genetic, epigenetic and environmental clues |journal= Trends Neurosci |volume=29 |issue=7 |pages=349–58 |year=2006 |pmid=16808981 |doi=10.1016/j.tins.2006.05.010}}</ref><ref>{{cite journal |journal= Int J Dev Neurosci |year=2007 |volume=25 |issue=2 |pages=69–85 |title= A review of gene linkage, association and expression studies in autism and an assessment of convergent evidence |author= Yang MS, Gill M |doi=10.1016/j.ijdevneu.2006.12.002 |pmid=17236739}}</ref> However, for most of the candidate genes, the actual mutations that increase the risk for autism have not been identified. Typically, autism cannot be traced to a [[Mendelian]] (single-gene) mutation or to single [[chromosome abnormalities]] such as [[fragile X syndrome]] or [[22q13 deletion syndrome]].<ref>{{cite journal |journal= J Autism Dev Disord |date=2005 |volume=35 |issue=1 |pages=103–16 |title= Specific genetic disorders and autism: clinical contribution towards their identification |author= Cohen D, Pichard N, Tordjman S ''et al.'' |doi=10.1007/s10803-004-1038-2 |pmid=15796126}}</ref><ref>{{cite journal |journal= Ment Retard Dev Disabil Res Rev |date=2007 |volume=13 |issue=1 |pages=85–95 |title= The study of autism as a distributed disorder |author= Müller RA |doi=10.1002/mrdd.20141 |pmid=17326118}}</ref> [[Image:Single Chromosome Mutations.png|thumb|Deletion (1), duplication (2) and inversion (3) are all [[chromosome abnormalities]] that have been implicated in autism.<ref name=Beaudet/>]] The large number of autistic individuals with unaffected family members may result from [[copy number variation]]s (CNVs)—spontaneous alterations in the genetic material during [[meiosis]] that [[Deletion (genetics)|delete]] or [[gene duplication|duplicate]] genetic material. Sporadic (non-inherited) cases have been examined to identify candidate [[Locus (genetics)|genetic loci]] involved in autism. Using [[array comparative genomic hybridization]] (array CGH), a technique for detecting CNVs, one study found them in 10% of families with one affected child.<ref>{{cite journal |author=Sebat J, Lakshmi B, Malhotra D ''et al.''|title=Strong association of de novo copy number mutations with autism |journal=Science |volume=316 |issue=5823 |pages=445–9 |year=2007 |pmid=17363630 |doi=10.1126/science.1138659}}</ref> Some of the altered loci had been identified in previous studies of inherited autism; many were unique to the sporadic cases examined in this study. Hence, a substantial fraction of autism may be highly heritable but not inherited: that is, the mutation that causes the autism is not present in the parental genome. Although the fraction of autism traceable to a genetic cause may grow to 30–40% as the resolution of array CGH improves,<ref name=Beaudet>{{cite journal |author= Beaudet AL |title= Autism: highly heritable but not inherited |journal= Nat Med |date=2007 |volume=13 |issue=5 |pages=534–6 |pmid=17479094 |doi=10.1038/nm0507-534}}</ref> several results in this area have been described incautiously, possibly misleading the public into thinking that a large proportion of autism is caused by CNVs and is detectable via array CGH, or that detecting CNVs is tantamount to a genetic diagnosis.<ref>{{cite journal |journal= Genet Med |year=2007 |volume=9 |issue=9 |pages=626–31 |title= Ethical implications of array comparative genomic hybridization in complex phenotypes: points to consider in research |author= Tabor HK, Cho MK |doi=10.1097/GIM.0b013e3181485688 |pmid=17873651}}</ref> The Autism Genome Project database contains [[genetic linkage]] and CNV data that connect autism to genetic loci and suggest that every human [[chromosome]] may be involved.<ref name=AGPC2007/> Though autism's genetic factors explain most of autism risk, they do not explain all of it. A common hypothesis is that autism is caused by the interaction of a genetic predisposition and an early environmental insult.<ref>{{cite journal |author= Trottier G, Srivastava L, Walker CD |title= Etiology of infantile autism: a review of recent advances in genetic and neurobiological research |journal= J Psychiatry Neurosci |date=1999 |volume=24 |issue=2 |pages=103–115 |pmid=10212552 |url=http://pubmedcentral.nih.gov/articlerender.fcgi?pubmedid=10212552}}</ref> Several theories based on environmental factors have been proposed to address the remaining risk. Some of these theories focus on prenatal environmental factors, such as agents that cause birth defects; others focus on the environment after birth, such as children's diets. ==Twin studies== [[Twin studies]] are a helpful tool in determining the [[heritability]] of disorders and human traits in general. They involve determining concordance of characteristics between identical ([[monozygotic]] or MZ) twins and between fraternal ([[dizygotic]] or DZ) twins. Possible problems of twin studies are: (1) errors in diagnosis of monozygocity, and (2) the assumption that social environment sharing by DZ twins is equivalent to that of MZ twins. A condition that is environmentally caused without genetic involvement would yield a concordance for MZ twins equal to the concordance found for DZ twins. In contrast, a condition that is completely genetic in origin would theoretically yield a concordance of 100% for MZ pairs and usually much less for DZ pairs depending on factors such as the number of genes involved and [[assortative mating]]. An example of a condition that appears to have very little if any genetic influence is [[irritable bowel syndrome]] (IBS), with a concordance of 28% vs. 27% for MZ and DZ pairs respectively.<ref name=genetics1>{{cite journal |author=Mohammed I, Cherkas LF, Riley SA, Spector TD, Trudgill NJ |title=Genetic influences in irritable bowel syndrome: a twin study |journal=Am. J. Gastroenterol. |volume=100 |issue=6 |pages=1340–4 |year=2005 |pmid=15929767 |doi=10.1111/j.1572-0241.2005.41700.x}}</ref> An example of a human characteristics that is extremely heritable is [[eye color]], with a concordance of 98% for MZ pairs and 7–49% for DZ pairs depending on age.<ref name=genetics2>{{cite journal |author=Bito LZ, Matheny A, Cruickshanks KJ, Nondahl DM, Carino OB |title=Eye color changes past early childhood. The Louisville Twin Study |journal=Arch. Ophthalmol. |volume=115 |issue=5 |pages=659–63 |year=1997 |pmid=9152135 |doi=}}</ref> Identical twin studies put autism's [[heritability]] in a range between 0.36 and 0.957, with concordance for a broader [[phenotype]] usually found at the higher end of the range.<ref name=twin>Twin studies (concordance in brackets): *(0.8–1) Ciaranello, Roland D. M.D[http://www.narsad.org/news/newsletter/specialreports/archautism.html The Neurobiology of Infantile Autism] *(0.8) Kallen, Ronald J. M.D [http://www.autism-biomed.org/bricktwn.htm CDC Reports a higher than expected prevalence of autism in Brick Township] *(0.91–0.93) Dawson, Geraldine Ph. D[http://faculty.washington.edu/dawson/Advocacy/Congress.html Written testimony Public Health Subcommittee, United States Senate] *(0.9) Lang, Leslie H.[http://www.parentsofallergicchildren.org/autism2.htm Study points to chromosome site of autism gene] *(0.6–0.92) {{cite journal |author=Muhle R, Trentacoste SV, Rapin I |title=The genetics of autism |journal=Pediatrics |volume=113 |issue=5 |pages=e472–86 |year=2004 |pmid=15121991 |doi=}} *(0.6–0.8) {{cite journal |author=Kurita H |title=[Current status of autism studies] |language=Japanese |journal=Seishin shinkeigaku zasshi &#61; Psychiatria et neurologia Japonica |volume=103 |issue=1 |pages=64–75 |year=2001 |pmid=11383012 |doi=}}</ref> Autism concordance in siblings and fraternal twins is anywhere between 0 and 23.5%. This is more likely 2–4% for classic autism and 10–20% for a broader spectrum. Assuming a general-population prevalence of 0.1%, the risk of classic autism in siblings is 20- to 40-fold that of the general population. Notable twin studies have attempted to shed light on the heritability of autism. A small scale study in 1977 was the first of its kind to look into the heritability of autism. It involved 10 DZ and 11 MZ pairs in which at least one twin in each pair showed infantile autism. It found a concordance of 36% in MZ twins compared to 0% for DZ twins. Concordance of "cognitive abnormalities" was 82% in MZ pairs and 10% for DZ pairs. In 12 of the 17 pairs discordant for autism, a biological hazard was believed to be associated with the condition.<ref>{{cite journal |author=Folstein S, Rutter M |title=Infantile autism: a genetic study of 21 twin pairs |journal=Journal of child psychology and psychiatry, and allied disciplines |volume=18 |issue=4 |pages=297–321 |year=1977 |pmid=562353 |doi=}}</ref> A 1979 case report discussed a pair of identical twins concordant for autism. The twins developed similarly until the age of 4, when one of them spontaneously improved. The other twin, who had suffered infrequent seizures, remained autistic. The report noted that genetic factors were not "all important" in the development of the twins.<ref name=genetics3>{{cite journal |author=Wessels WH, Pompe van Meerdervoort M |title=Monozygotic twins with early infantile autism. A case report |journal=S. Afr. Med. J. |volume=55 |issue=23 |pages=955–7 |year=1979 |pmid=572995 |doi=}}</ref> In 1985, a study of twins enrolled with the UCLA Registry for Genetic Studies found a concordance of 95.7% for autism in 23 pairs of MZ twins, and 23.5% for 17 DZ twins.<ref name=genetics4>{{cite journal |author=Ritvo ER, Freeman BJ, Mason-Brothers A, Mo A, Ritvo AM |title=Concordance for the syndrome of autism in 40 pairs of afflicted twins |journal=The American journal of psychiatry |volume=142 |issue=1 |pages=74–7 |year=1985 |pmid=4038442 |doi=}}</ref> In a 1989 study, [[Nordic countries]] were screened for cases of autism. Eleven pairs of MZ twins and 10 of DZ twins were examined. Concordance of autism was found to be 91% in MZ and 0% in DZ pairs. The concordances for "cognitive disorder" were 91% and 30% respectively. In most of the pairs discordant for autism, the autistic twin had more perinatal stress.<ref name=genetics5>{{cite journal |author=Steffenburg S, Gillberg C, Hellgren L, ''et al'' |title=A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden |journal=Journal of child psychology and psychiatry, and allied disciplines |volume=30 |issue=3 |pages=405–16 |year=1989 |pmid=2745591 |doi=}}</ref> A British twin sample was reexamined in 1995 and a 60% concordance was found for autism in MZ twins vs. 0% concordance for DZ. It also found 92% concordance for a broader spectrum in MZ vs. 10% for DZ. The study concluded that "obstetric hazards usually appear to be consequences of genetically influenced abnormal development, rather than independent aetiological factors."<ref>{{cite journal |author=Bailey A, Le Couteur A, Gottesman I, ''et al'' |title=Autism as a strongly genetic disorder: evidence from a British twin study |journal=Psychological medicine |volume=25 |issue=1 |pages=63–77 |year=1995 |pmid=7792363 |doi=}}</ref> A 1999 study looked at social cognitive skills in general-population children and adolescents. It found "poorer social cognition in males", and a heritability of 0.68 with higher genetic influence in younger twins.<ref>{{cite journal |author=Scourfield J, Martin N, Lewis G, McGuffin P |title=Heritability of social cognitive skills in children and adolescents |journal=The [[British Journal of Psychiatry]] : the journal of mental science |volume=175 |issue= |pages=559–64 |year=1999 |pmid=10789354 |doi=}}</ref> In 2000, a study looked at reciprocal social behavior in general-population identical twins. It found a concordance of 73% for MZ, i.e. "highly heritable", and 37% for DZ pairs.<ref>{{cite journal |author=Constantino JN, Todd RD |title=Genetic structure of reciprocal social behavior |journal=The American journal of psychiatry |volume=157 |issue=12 |pages=2043–5 |year=2000 |pmid=11097975 |doi=}}</ref> A 2004 study looked at 16 MZ twins and found a concordance of 43.75% for "strictly defined autism". Neuroanatomical differences (discordant cerebellar white and grey matter volumes) between discordant twins were found. The abstract notes that in previous studies 75% of the non-autistic twins displayed the broader [[phenotype]].<ref>{{cite journal |author=Kates WR, Burnette CP, Eliez S, ''et al'' |title=Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism |journal=The American journal of psychiatry |volume=161 |issue=3 |pages=539–46 |year=2004 |pmid=14992981 |doi=}}</ref> Another 2004 study examined whether the characteristic symptoms of autism (impaired social interaction, communication deficits, and repetitive behaviors) show decreased variance of symptoms among [[monozygotic]] twins compared to siblings in a sample of 16 families. The study demonstrated significant aggregation of symptoms in twins. It also concluded that "the levels of clinical features seen in autism may be a result of mainly independent genetic traits."<ref>{{cite journal |author=Kolevzon A, Smith CJ, Schmeidler J, Buxbaum JD, Silverman JM |title=Familial symptom domains in monozygotic siblings with autism |journal=Am. J. Med. Genet. B Neuropsychiatr. Genet. |volume=129 |issue=1 |pages=76–81 |year=2004 |pmid=15274045 |doi=10.1002/ajmg.b.30011}}</ref> An English twin study in 2006 found high heritability for autistic traits in a large group of 3,400 pairs of twins.<ref>{{cite journal |author=Ronald A, Happé F, Bolton P, ''et al'' |title=Genetic heterogeneity between the three components of the autism spectrum: a twin study |journal=Journal of the American Academy of Child and Adolescent Psychiatry |volume=45 |issue=6 |pages=691–9 |year=2006 |pmid=16721319 |doi=10.1097/01.chi.0000215325.13058.9d}}</ref> One critic of the pre-2006 twin studies said that they were too small and their results can be plausibly explained on non-genetic grounds.<ref>{{cite book|chapter=Autism and genetics: much ado about very little|url=http://www.jayjoseph.net/MissingGeneChapters.html|accessdate=2007-07-25|author=Joseph J|title=The Missing Gene: Psychiatry, Heredity, and the Fruitless Search for Genes|date=2006|publisher=Algora|isbn=0875864104}}</ref> ==Sibling studies== The importance of sibling studies lies in contrasting their results to those of fraternal (DZ) twin studies, plus their sample sizes can be much larger. Environment sharing by siblings is presumably different enough to that of DZ twins to shed some light on the magnitude of environmental influence. This should even be true to some extent regarding the prenatal environment. Unfortunately DZ twin study findings have yielded a very large range of variance and are error prone because of the apparent low concordance and the fact that they typically look at a small number of DZ pairs. For example, in studies involving 10 DZ pairs, a concordance below 10% would be impossible to determine precisely.{{Fact|date=February 2007}} A study of 99 autistic probands which found a 2.9% concordance for autism in siblings, and between 12.4% and 20.4% concordance for a "lesser variant" of autism.<ref name=Bolton>{{cite journal |journal= J Child Psychol Psychiatry |year=1994 |volume=35 |issue=5 |pages=877–900 |title= A case-control family history study of autism |author= Bolton P, Macdonald H, Pickles A ''et al.'' |doi=10.1111/j.1469-7610.1994.tb02300.x |pmid=7962246}}</ref> A study of 31 siblings of autistic children, 32 siblings of children with developmental delay, and 32 controls. It found that the siblings of autistic children, as a group, "showed superior spatial and verbal span, but a greater than expected number performed poorly on the set-shifting, planning, and verbal fluency tasks."<ref>{{cite journal |author=Hughes C, Plumet MH, Leboyer M |title=Towards a cognitive phenotype for autism: increased prevalence of executive dysfunction and superior spatial span amongst siblings of children with autism |journal=Journal of child psychology and psychiatry, and allied disciplines |volume=40 |issue=5 |pages=705–18 |year=1999 |pmid=10433405 |doi=}}</ref> A 2005 Danish study looked at "data from the Danish Psychiatric Central Register and the Danish Civil Registration System to study some risk factors of autism, including place of birth, parental place of birth, parental age, family history of psychiatric disorders, and paternal identity." It found an overall prevalence rate of roughly 0.08%. Prevalence of autism in siblings of autistic children was found to be 1.76%. Prevalence of autism among siblings of children with [[Asperger's syndrome]] or [[PDD]] was found to be 1.04%. The risk was twice as high if the mother had been diagnosed with a psychiatric disorder. The study also found that "the risk of autism was associated with increasing degree of urbanisation of the child's place of birth and with increasing paternal, but not maternal, age."<ref>{{cite journal |author=Lauritsen MB, Pedersen CB, Mortensen PB |title=Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study |journal=Journal of child psychology and psychiatry, and allied disciplines |volume=46 |issue=9 |pages=963–71 |year=2005 |pmid=16108999 |doi=10.1111/j.1469-7610.2004.00391.x}}</ref> A study in 2007 looked at a database containing pedigrees of 86 families with two or more autistic children and found that 42 of the third-born male children showed autistic symptoms, suggesting that parents had a 50% chance of passing on a mutation to their offspring. The mathematical models suggest that about 50% of autistic cases are caused by spontaneous mutations. The simplest model was to divide parents into two risk classes depending on whether the parent carries a pre-existing mutation that causes autism; it suggested that about a quarter of autistic children have inherited a [[copy number variation]] from their parents.<ref name=Zhao>{{cite journal |author=Zhao X, Leotta A, Kustanovich V, ''et al'' |title=A unified genetic theory for sporadic and inherited autism |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=104 |issue=31 |pages=12831–6 |year=2007 |pmid=17652511 |doi=10.1073/pnas.0705803104|url=http://www.pnas.org/cgi/content/full/104/31/12831|laysummary=http://www.cshl.edu/public/releases/07_new_autism_model.html|laysource=CSHL|laydate=2007-07-23}}</ref> ==Other family studies== A 1994 looked at the personalities of parents of autistic children, using parents of children with [[Down's syndrome]] as controls. Using standardized tests it was found that parents of autistic children were "more aloof, untactful and unresponsive."<ref>{{cite journal |author=Piven J, Wzorek M, Landa R, ''et al'' |title=Personality characteristics of the parents of autistic individuals |journal=Psychological medicine |volume=24 |issue=3 |pages=783–95 |year=1994 |pmid=7991760 |doi=}}</ref> A 1997 study found higher rates of social and communication deficits and stereotyped behaviors in families with multiple-incidence autism.<ref>{{cite journal |author=Piven J, Palmer P, Jacobi D, Childress D, Arndt S |title=Broader autism phenotype: evidence from a family history study of multiple-incidence autism families |journal=The American journal of psychiatry |volume=154 |issue=2 |pages=185–90 |year=1997 |pmid=9016266 |doi=}}</ref> Autism was found to occur more often in families of physicists, engineers and scientists.<ref>Baron-Cohen S, Bolton P, Wheelwright S, et al. [http://www.autismresearchcentre.com/docs/papers/1998_BCetal_Maths.pdf "Autism occurs more often in families of physicists, engineers, and mathematicians". (PDF}] ''Autism'', 1998, 2, 296-301. Retrieved December 10, 2006.</ref> Other studies have yielded similar results.<ref>Baron-Cohen S, Wheelwright S, Stott C, et al. [http://www.autismresearchcentre.com/docs/papers/1997_BCetal_Engineer.pdf "Is there a link between engineering and autism?" (PDF)] ''Autism'', 1997, 1, 153-163. Retrieved December 10, 2006.</ref><ref>{{cite journal |author=Wheelwright S, Baron-Cohen S |title=The link between autism and skills such as engineering, maths, physics and computing: a reply to Jarrold and Routh |journal=Autism : the international journal of research and practice |volume=5 |issue=2 |pages=223–7 |year=2001 |pmid=11706868 |doi=}}[http://aut.sagepub.com/cgi/content/abstract/5/2/223 Online.]</ref> Findings of this nature have led to the coinage of the term "geek syndrome".<ref>Silberman, Steve. [http://www.wired.com/wired/archive/9.12/aspergers_pr.html The Geek Syndrome.] ''Wired Magazine'' (December 2001). Retrieved on [[December 10]], [[2006]].</ref> A 2001 study of brothers and parents of autistic boys looked into the [[phenotype]] in terms of one current cognitive theory of autism. The study raised the possibility that the broader autism phenotype may include a "cognitive style" (weak central coherence) that can confer information-processing advantages.<ref>{{cite journal |author=Happé F, Briskman J, Frith U |title=Exploring the cognitive phenotype of autism: weak "central coherence" in parents and siblings of children with autism: I. Experimental tests |journal=Journal of child psychology and psychiatry, and allied disciplines |volume=42 |issue=3 |pages=299–307 |year=2001 |pmid=11321199 |doi=}}</ref> A study in 2005 showed a positive correlation between repetitive behaviors in autistic individuals and obsessive-compulsive behaviors in parents.<ref>{{cite journal |author=Abramson RK, Ravan SA, Wright HH, ''et al'' |title=The relationship between restrictive and repetitive behaviors in individuals with autism and obsessive compulsive symptoms in parents |journal=Child psychiatry and human development |volume=36 |issue=2 |pages=155–65 |year=2005 |pmid=16228144 |doi=10.1007/s10578-005-2973-7}}</ref> Another 2005 study focused on sub-threashold autistic traits in the general population. It found that correlation for social impairment or competence between parents and their children and between spouses is about 0.4.<ref>{{cite journal |author=Constantino JN, Todd RD |title=Intergenerational transmission of subthreshold autistic traits in the general population |journal=Biol. Psychiatry |volume=57 |issue=6 |pages=655–60 |year=2005 |pmid=15780853 |doi=10.1016/j.biopsych.2004.12.014}}</ref> A 2005 report examined the family psychiatric history of 58 subjects with [[Asperger's syndrome]] (AS) diagnosed according to [[DSM-IV]] criteria. Three (5%) had first-degree relatives with AS. Nine (19%) had a family history of [[schizophrenia]]. Thirty five (60%) had a family history of [[clinical depression|depression]]. Out of 64 siblings, 4 (6.25%) were diagnosed with AS.<ref>{{cite journal |author=Ghaziuddin M |title=A family history study of Asperger syndrome |journal=Journal of autism and developmental disorders |volume=35 |issue=2 |pages=177–82 |year=2005 |pmid=15909404 |doi=}}</ref> ==Twinning risk== It has been suggested that the twinning process itself is a risk factor in the development of autism, presumably due to perinatal factors.<ref>{{cite journal |author=Greenberg DA, Hodge SE, Sowinski J, Nicoll D |title=Excess of twins among affected sibling pairs with autism: implications for the etiology of autism |journal=Am. J. Hum. Genet. |volume=69 |issue=5 |pages=1062–7 |year=2001 |pmid=11590546 |doi=}}</ref> However, three large-scale epidemiological studies have refuted this idea.<ref>{{cite journal |author=Hallmayer J, Glasson EJ, Bower C, ''et al'' |title=On the twin risk in autism |journal=Am. J. Hum. Genet. |volume=71 |issue=4 |pages=941–6 |year=2002 |pmid=12297988 |doi=}}</ref><ref name=Freitag>{{cite journal |author= Freitag CM |title= The genetics of autistic disorders and its clinical relevance: a review of the literature |journal= Mol Psychiatry |volume=12 |issue=1 |pages=2–22 |date=2007 |doi=10.1038/sj.mp.4001896 |pmid=17033636 |url=http://www.nature.com/mp/journal/v12/n1/full/4001896a.html}}</ref> ==Phenocopies== Evidence has mounted indicating that clinical pictures that look like autism ([[phenocopies]]) may not be due to the same genetic liability. Examples are congenital [[blindness]],<ref>{{cite journal |author=Hobson RP, Lee A, Brown R |title=Autism and congenital blindness |journal=Journal of autism and developmental disorders |volume=29 |issue=1 |pages=45–56 |year=1999 |pmid=10097994 |doi=}}</ref> profound institutional privation,<ref>{{cite journal |author=Hoksbergen R, ter Laak J, Rijk K, van Dijkum C, Stoutjesdijk F |title=Post-Institutional Autistic Syndrome in Romanian adoptees |journal=Journal of autism and developmental disorders |volume=35 |issue=5 |pages=615–23 |year=2005 |pmid=16167089 |doi=10.1007/s10803-005-0005-x}}</ref><ref>{{cite journal |author=Rutter ML, Kreppner JM, O'Connor TG |title=Specificity and heterogeneity in children's responses to profound institutional privation |journal=The British Journal of Psychiatry : the journal of mental science |volume=179 |issue= |pages=97–103 |year=2001 |pmid=11483469 |doi=}}</ref> and a number of conditions related to mental retardation.<ref>{{cite journal |author=Rutter M, Bailey A, Bolton P, Le Couteur A |title=Autism and known medical conditions: myth and substance |journal=Journal of child psychology and psychiatry, and allied disciplines |volume=35 |issue=2 |pages=311–22 |year=1994 |pmid=8188801 |doi=}}</ref> [[Fragile-X syndrome]], [[Rett syndrome]] and [[tuberous sclerosis]] are well-known causes of autism-like symptoms. ==Proposed models== Twin and family studies show that autism is a highly heritable condition, but they have left many questions for researchers, most notably * Why is fraternal twin concordance so low considering that identical twin concordance is high? * Why are parents of autistic children typically non-autistic? * Which factors could be involved in the failure to find a 100% concordance in identical twins? * Is profound mental retardation a characteristic of the [[genotype]] or something totally independent? Some researchers have speculated that what we currently refer to as "autism" may be a catch-all description for many yet unknown conditions with different genetic and/or environmental etiologies. This would appear to make the effort to find a [[genotype]] model a lot more difficult, and perhaps even pointless. Nevertheless, a number of genetic models have been proposed to try to explain the results of twin and sibling studies. ===Mendelian=== The original [[Mendelian inheritance|Mendelian model]] tried to explain observations using distinct genes existing in clearly dominant or recessive [[allele]]s. That would imply a recessive "autism gene" inherited from each of the parents. This kind of model is clearly too simple:<ref>[http://www.webpediatrics.com/autism.html Autism and Autistic Spectrum Disorders Genetic origin: is there an "autism" gene?] WebPediatrics.com. Retrieved on [[March 2]], [[2007]]. </ref> * It indicates that a sibling of an autistic individual should have 25% risk of having the autistic [[genotype]], which is inconsistent with fraternal twin and sibling study results. * It would require several characteristic features of autism to be caused by a single [[allele]] at a single locus. Further considerations for the 'autism gene model' of also show contradictory implications: *(a) only a small number of cases can be clearly linked to a possible genetic cause and these are often [[allele]] deletions; *(b) the majority of patients with autism do not marry and do not have offspring which should result in a decreased incidence of the presumed gene in the general population. *(c) the incidence of autism in the population has been increasing instead, making the likelihood of a single genetic cause extremely remote. Mendel's later work and work based on it introduced polygenic inheritance, but taking into account linkage of genes required understanding where they were located - elucidating the role of the [[chromosomes]]{{Fact|date=February 2007}}<!-- whenever that was - add a date here -->. ===Multigene=== Reduced risk to relatives of probands and identical/fraternal twin ratios indicate that a multigene model is more likely to account for the autistic [[genotype]]. That is, at least two [[allele]]s would be involved, and most likely three to five. Researchers have suggested models of 15 and even up to 100 genes.{{Fact|date=February 2007}} The fraternal twin results found by Ritvo et al (1985)<ref name=genetics4/> and the broader phenotype results of Bolton et al (1994)<ref name=Bolton/> suggest that a 2-gene model is plausible. Kolevzon et al (2004) proposed that the 3 characteristic symptoms of autism may be the result of 3 different [[allele]]s.{{Fact|date=February 2007}} Data supports the multiple-[[locus (genetics)|locus]] hypothesis and also that a 3-loci model is the best fit.<ref>{{cite journal |author=Pickles A, Bolton P, Macdonald H, ''et al'' |title=Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism |journal=Am. J. Hum. Genet. |volume=57 |issue=3 |pages=717–26 |year=1995 |pmid=7668301 |doi=}}</ref> Risch et al (1999) found results most compatible with a large number of loci (>= 15).<ref>{{cite journal |author=Risch N, Spiker D, Lotspeich L, ''et al'' |title=A genomic screen of autism: evidence for a multilocus etiology |journal=Am. J. Hum. Genet. |volume=65 |issue=2 |pages=493–507 |year=1999 |pmid=10417292 |doi=}}</ref> Given the significant prevalence of autism, perhaps 0.1% for classic autism and at least 0.6% for a broader spectrum,{{Fact|date=February 2007}} a multigene model has important implications. Since intelligence appears to be independent of the recognized characteristic symptoms of autism (and the diagnostic criteria) it is likely that many individuals are very autistic yet highly functional, allowing them to escape a diagnosis altogether.{{Fact|date=February 2007}} So the prevalence of the autistic genotype may be considerably higher than thought. And if multiple alleles are part of the genotype, then each allele must have relatively high prevalence in the general population.{{Fact|date=February 2007}} ===Two family types=== In this model most families fall into two types: in the majority, sons have a low risk of autism, but in a small minority their risk is near 50%. In the low-risk families, sporadic autism is mainly caused by spontaneous [[mutation]] with poor [[penetrance]] in daughters and high penetrance in sons. The high-risk families come from (mostly female) children who carry a new causative mutation but are unaffected and transmit the dominant mutation to grandchildren.<ref name=Zhao/> ===Epigenetic=== Several [[epigenetic]] models of autism have been proposed.<ref>{{cite journal |author=Jiang YH, Sahoo T, Michaelis RC, ''et al'' |title=A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A |journal=Am. J. Med. Genet. A |volume=131 |issue=1 |pages=1–10 |year=2004 |pmid=15389703 |doi=10.1002/ajmg.a.30297}}</ref> These are suggested by the occurrence of autism in individuals with fragile X syndrome, which arises from epigenetic mutations, and with Rett syndrome, which involves epigenetic regulatory factors. An epigenetic model would help explain why standard genetic screening strategies have so much difficulty with autism.<ref>{{cite journal |journal= Hum Mol Genet |date=2006 |volume=15 |issue= Review 2 |pages=R138–50 |title= Epigenetics of autism spectrum disorders |author= Schanen NC |doi=10.1093/hmg/ddl213 |pmid=16987877 |url=http://hmg.oxfordjournals.org/cgi/content/full/15/suppl_2/R138}}</ref> ===Genomic imprinting=== [[Genomic imprinting]] models have been proposed; one of their strengths is explaining the high male-to-female ratio in ASD.<ref>{{cite journal |author=Skuse DH |title=Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism |journal=Pediatr. Res. |volume=47 |issue=1 |pages=9–16 |year=2000 |pmid=10625077 |doi=}}</ref> One hypothesis is that autism is in some sense diametrically opposite to [[schizophrenia]] and other psychotic-spectrum conditions, that alterations of genomic imprinting help to mediate the development of these two sets of conditions, and that ASD involves increased effects of paternally expressed genes, which regulate overgrowth in the brain, whereas schizophrenia involves maternally expressed genes and undergrowth.<ref>{{cite journal |journal= Behav Brain Sci |date=2008 |volume=31 |issue=3 |pages=241–61 |title= Psychosis and autism as diametrical disorders of the social brain |author= Crespi B, Badcock C |doi=10.1017/S0140525X08004214 |pmid=18578904}}</ref> ==Candidate gene loci== A number of [[allele]]s have been shown to have strong linkage to the autism [[phenotype]]. In many cases the findings are inconclusive, with some studies showing no linkage. Alleles linked so far strongly support the assertion that there is a large number of [[genotype]]s that are manifested as the autism [[phenotype]]. At least some of the alleles associated with autism are fairly prevalent in the general population, which indicates they are not rare pathogenic mutations. This also presents some challenges in identifying all the rare allele ''combinations'' involved in the etiology of autism. ===Primary=== {| class="wikitable" | '''Gene''' || '''[[Locus (genetics)|Locus]]''' || '''Description''' |- | ? || 16p11.2 || A 2008 study observed a de novo deletion of 593 kb on this chromosome in about 1% of persons with autism, and similarly for the reciprocal duplication of the region.<ref>{{cite journal |journal= N Engl J Med |year=2008 |volume=358 |issue=7 |pages=667–75 |title= Association between microdeletion and microduplication at 16p11.2 and autism |author= Weiss LA, Shen Y, Korn JM ''et al.'' |doi=10.1056/NEJMoa075974 |pmid=18184952 |url=http://content.nejm.org/cgi/content/full/NEJMoa075974 |laysummary=http://www.boston.com/news/health/blog/2008/01/boston_research.html |laysource= Boston Globe |laydate=2008-01-09}}</ref> Another 2008 study also found duplications and deletions associated with ASD at this locus.<ref>{{cite journal |journal= Am J Hum Genet |date=2008 |volume=82 |issue=2 |pages=477–88 |title= Structural variation of chromosomes in autism spectrum disorder |author= Marshall CR, Noor A, Vincent JB ''et al.'' |pmid=18252227 |doi=10.1016/j.ajhg.2007.12.009 |url=http://www.ajhg.org/AJHG/fulltext/S0002-9297(07)00035-3 |laysummary=http://www.medpagetoday.com/Neurology/Autism/tb/8013 |laysource= MedPage Today |laydate=2008-01-17}}</ref> |- | SERT ([[SLC6A4]]) || 17q11.2 || This gene locus has been associated with rigid-compulsive behaviors. Notably, it has also been associated with [[clinical depression|depression]] but only as a result of social adversity, although other studies have found no link.<ref>{{cite journal |author=Surtees PG, Wainwright NW, Willis-Owen SA, Luben R, Day NE, Flint J |title=Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder |journal=Biol. Psychiatry |volume=59 |issue=3 |pages=224–9 |year=2006 |pmid=16154545 |doi=10.1016/j.biopsych.2005.07.014}}</ref> Significant linkage in families with only affected males has been shown.<ref>{{cite journal |author=Sutcliffe JS, Delahanty RJ, Prasad HC, ''et al'' |title=Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors |journal=Am. J. Hum. Genet. |volume=77 |issue=2 |pages=265–79 |year=2005 |pmid=15995945 |doi=10.1086/432648}}</ref><ref>{{cite journal |author=Devlin B, Cook EH, Coon H, ''et al'' |title=Autism and the serotonin transporter: the long and short of it |journal=Mol. Psychiatry |volume=10 |issue=12 |pages=1110–6 |year=2005 |pmid=16103890 |doi=10.1038/sj.mp.4001724}}</ref> Researchers have also suggested that the gene contributes to [[serotonin syndrome|hyperserotonemia]].<ref>{{cite journal |author=Coutinho AM, Oliveira G, Morgadinho T, ''et al'' |title=Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism |journal=Mol. Psychiatry |volume=9 |issue=3 |pages=264–71 |year=2004 |pmid=15094787 |doi=10.1038/sj.mp.4001409}}</ref> However, a 2008 meta-analysis of family- and population-based studies found no significant overall association between autism and either the promoter insertion/deletion ([[5-HTTLPR]]) or the intron 2 VNTR (STin2 VNTR) polymorphisms.<ref>{{cite journal |journal= Am J Med Genet B Neuropsychiatr Genet |date=2008 |title= Autism and serotonin transporter gene polymorphisms: a systematic review and meta-analysis |author= Huang CH, Santangelo SL |doi=10.1002/ajmg.b.30720 |pmid=18286633}}</ref> |- | [[GABRB3]], [[GABRA4]] || multiple || [[GABA]] is the primary inhibitory [[neurotransmitter]] of the human brain. Ma et al (2005) concluded that [[GABRA4]] is involved in the etiology of autism, and that it potentially increases autism risk through interaction with GABRB1.<ref>{{cite journal |author=Ma DQ, Whitehead PL, Menold MM, ''et al'' |title=Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism |journal=Am. J. Hum. Genet. |volume=77 |issue=3 |pages=377–88 |year=2005 |pmid=16080114 |doi=10.1086/433195}}</ref> The [[GABRB3]] gene has been associated with [[savant]] skills.<ref name=PMID12819446>{{cite journal |author=Nurmi EL, Dowd M, Tadevosyan-Leyfer O, Haines JL, Folstein SE, Sutcliffe JS |title=Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11-q13 |journal=Journal of the American Academy of Child and Adolescent Psychiatry |volume=42 |issue=7 |pages=856–63 |year=2003 |pmid=12819446 |doi=10.1097/01.CHI.0000046868.56865.0F}}</ref> The GABRB3 gene deficient mouse has been proposed as a model of ASD.<ref>{{cite journal |author=Delorey TM, Sahbaie P, Hashemi E, Homanics GE, Clark JD |title=Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: A potential model of autism spectrum disorder |journal= Behav Brain Res |volume=187 |issue=2 |pages=207–20 |year=2007 |pmid=17983671 |doi=10.1016/j.bbr.2007.09.009}}</ref> |- | [[Engrailed 2]] (EN2) || 7q36.2 || Engrailed 2 is believed to be associated with [[cerebellum|cerebellar]] development. Benayed et al (2005) estimate that this gene contributes to as many as 40% of ASD cases, about twice the prevalence of the general population.<ref>{{cite journal |author=Benayed R, Gharani N, Rossman I, ''et al'' |title=Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus |journal=Am. J. Hum. Genet. |volume=77 |issue=5 |pages=851–68 |year=2005 |pmid=16252243 |doi=10.1086/497705}}</ref> But at least one study has found no association.<ref>{{cite journal |author=Zhong H, Serajee FJ, Nabi R, Huq AH |title=No association between the EN2 gene and autistic disorder |journal=J. Med. Genet. |volume=40 |issue=1 |pages=e4 |year=2003 |pmid=12525552 |doi=}}</ref> |- | ? || 3q25-27 || A number of studies have shown a significant linkage of autism and [[Asperger's syndrome]] with this locus.<ref>{{cite journal |author=Auranen M, Varilo T, Alen R, ''et al'' |title=Evidence for allelic association on chromosome 3q25-27 in families with autism spectrum disorders originating from a subisolate of Finland |journal=Mol. Psychiatry |volume=8 |issue=10 |pages=879–84 |year=2003 |pmid=14515138 |doi=10.1038/sj.mp.4001299}}</ref><ref>{{cite journal |author=Ylisaukko-oja T, Nieminen-von Wendt T, Kempas E, ''et al'' |title=Genome-wide scan for loci of Asperger syndrome |journal=Mol. Psychiatry |volume=9 |issue=2 |pages=161–8 |year=2004 |pmid=14966474 |doi=10.1038/sj.mp.4001385}}</ref> The most prominent markers are in the vicinity of D3S3715 and D3S3037.<ref>{{cite journal |author=Auranen M, Vanhala R, Varilo T, ''et al'' |title=A genomewide screen for autism-spectrum disorders: evidence for a major susceptibility locus on chromosome 3q25-27 |journal=Am. J. Hum. Genet. |volume=71 |issue=4 |pages=777–90 |year=2002 |pmid=12192642 |doi=}}</ref> |- | [[Reelin]] || 7q21-q36|| In adults, [[Reelin]] [[glycoprotein]] is believed to be involved in memory formation, neurotransmission, and synaptic plasticity. A number of studies have shown an association between the REELIN gene and autism,<ref>{{cite journal |author=Serajee FJ, Zhong H, Mahbubul Huq AH |title=Association of Reelin gene polymorphisms with autism |journal=Genomics |volume=87 |issue=1 |pages=75–83 |year=2006 |pmid=16311013 |doi=10.1016/j.ygeno.2005.09.008}}</ref><ref>{{cite journal |author=Skaar DA, Shao Y, Haines JL, ''et al'' |title=Analysis of the RELN gene as a genetic risk factor for autism |journal=Mol. Psychiatry |volume=10 |issue=6 |pages=563–71 |year=2005 |pmid=15558079 |doi=10.1038/sj.mp.4001614}}</ref> but a couple of studies were unable to duplicate linkage findings.<ref>{{cite journal |author=Li J, Nguyen L, Gleason C, ''et al'' |title=Lack of evidence for an association between WNT2 and RELN polymorphisms and autism |journal=Am. J. Med. Genet. B Neuropsychiatr. Genet. |volume=126 |issue=1 |pages=51–7 |year=2004 |pmid=15048648 |doi=10.1002/ajmg.b.20122}}</ref> |- | [[SLC25A12]] || 2q31 || This gene encodes the [[mitochondria]]l [[aspartate]]/[[glutamate]] carrier (AGC1). It has been found to have a significant linkage to autism in some studies,<ref>{{cite journal |author=Segurado R, Conroy J, Meally E, Fitzgerald M, Gill M, Gallagher L |title=Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31 |journal=The American journal of psychiatry |volume=162 |issue=11 |pages=2182–4 |year=2005 |pmid=16263864 |doi=10.1176/appi.ajp.162.11.2182}}</ref><ref>{{cite journal |author=Ramoz N, Reichert JG, Smith CJ, ''et al'' |title=Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism |journal=The American journal of psychiatry |volume=161 |issue=4 |pages=662–9 |year=2004 |pmid=15056512 |doi=}}</ref><ref>{{cite journal |journal= Mol Psychiatry |date=2008 |volume=13 |issue=4 |pages=385–97 |title= SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects |author= Lepagnol-Bestel AM, Maussion G, Boda B ''et al.'' |pmid=18180767 |doi=10.1038/sj.mp.4002120}}</ref> but linkage was not replicated in others,<ref>{{cite journal |author=Blasi F, Bacchelli E, Carone S, ''et al'' |title=SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample |journal=Eur. J. Hum. Genet. |volume=14 |issue=1 |pages=123–6 |year=2006 |pmid=16205742 |doi=10.1038/sj.ejhg.5201444}}</ref> and a 2007 study found no compelling evidence of an association of any [[Human mitochondrial DNA haplogroup|mitochondrial haplogroup]] in autism.<ref>{{cite journal |journal= Am J Med Genet B Neuropsychiatr Genet |date=2007 |title= An investigation of mitochondrial haplogroups in autism |author= Kent L, Gallagher L, Elliot HR, Mowbray C, Chinnery PF |doi=10.1002/ajmg.b.30687 |pmid=18161860}}</ref> |- | [[HOXA1]] and [[HOXB1]] || multiple || A link has been found between HOX genes and the development of the embryonic brain stem. In particular, two genes, HOXA1 and HOXB1, in transgenic 'knockout' mice, engineered so that these genes were absent from the genomes of the mice in question, exhibited very specific brain stem developmental differences from the norm, which were directly comparable to the brain stem differences discovered in a human brain stem originating from a diagnosed autistic patient.<ref>{{cite journal |author=Rodier PM |title=The early origins of autism |journal=Sci. Am. |volume=282 |issue=2 |pages=56–63 |year=2000 |pmid=10710787 |doi=}}</ref> Conciatori et al (2004) found an association of HOXA1 with increased head circumference.<ref>{{cite journal |author=Conciatori M, Stodgell CJ, Hyman SL, ''et al'' |title=Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism |journal=Biol. Psychiatry |volume=55 |issue=4 |pages=413–9 |year=2004 |pmid=14960295 |doi=10.1016/j.biopsych.2003.10.005}}</ref> A number of studies have found no association with autism.<ref>{{cite journal |author=Gallagher L, Hawi Z, Kearney G, Fitzgerald M, Gill M |title=No association between allelic variants of HOXA1/HOXB1 and autism |journal=Am. J. Med. Genet. B Neuropsychiatr. Genet. |volume=124 |issue=1 |pages=64–7 |year=2004 |pmid=14681917 |doi=10.1002/ajmg.b.20094}}</ref><ref>{{cite journal |author=Collins JS, Schroer RJ, Bird J, Michaelis RC |title=The HOXA1 A218G polymorphism and autism: lack of association in white and black patients from the South Carolina Autism Project |journal=Journal of autism and developmental disorders |volume=33 |issue=3 |pages=343–8 |year=2003 |pmid=12908836 |doi=}}</ref><ref>{{cite journal |author=Talebizadeh Z, Bittel DC, Miles JH, ''et al'' |title=No association between HOXA1 and HOXB1 genes and autism spectrum disorders (ASD) |journal=J. Med. Genet. |volume=39 |issue=11 |pages=e70 |year=2002 |pmid=12414832 |doi=}}</ref> The possibility remains that single allelic variants of the HOXA1 gene are insufficient alone to trigger the developmental events in the embryo now associated with autistic spectrum conditions. Tischfield ''et al'' published a paper which suggests that because HOXA1 is implicated in a wide range of developmental mechanisms, a model involving multiple allelic variants of HOXA1 in particular may provide useful insights into the heritability mechanisms involved.<ref>{{cite journal |author=Tischfield MA, Bosley TM, Salih MA, ''et al'' |title=Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development |journal=Nat. Genet. |volume=37 |issue=10 |pages=1035–7 |year=2005 |pmid=16155570 |doi=10.1038/ng1636}}</ref> Additionally, Ingram ''et al'' alighted upon additional possibilities in this arena.<ref>{{cite journal |author=Ingram JL, Stodgell CJ, Hyman SL, Figlewicz DA, Weitkamp LR, Rodier PM |title=Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders |journal=Teratology |volume=62 |issue=6 |pages=393–405 |year=2000 |pmid=11091361 |doi=10.1002/1096-9926(200012)62:6<393::AID-TERA6>3.0.CO;2-V}}</ref> Transgenic mouse studies indicate that there is redundancy spread across HOX genes that complicate the issue, and that complex interactions between these genes could play a role in determining whether or not a person inheriting the requisite combinations manifests an autistic spectrum condition<ref>{{cite journal |author=Rossel M, Capecchi MR |title=Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development |journal=Development |volume=126 |issue=22 |pages=5027–40 |year=1999 |pmid=10529420 |doi=}}</ref>—transgenic mice with mutations in both HOXA1 and HOXB1 exhibit far more profound developmental anomalies than those in which only one of the genes differs from the conserved 'norm'. In Rodier's original work, teratogens are considered to play a part in addition, and that the possibility remains open for a range of teratogens to interact with the mechanisms controlled by these genes unfavourably (this has already been demonstrated using valproic acid, a known teratogen, in the mouse model).{{Fact|date=February 2007}} |- | [[PRKCB1]] || 16p11.2 || Philippi et al (2005) found a strong association between this gene and autism. This is a recent finding that needs to be replicated.<ref>{{cite journal |author=Philippi A, Roschmann E, Tores F, ''et al'' |title=Haplotypes in the gene encoding protein kinase c-beta (PRKCB1) on chromosome 16 are associated with autism |journal=Mol. Psychiatry |volume=10 |issue=10 |pages=950–60 |year=2005 |pmid=16027742 |doi=10.1038/sj.mp.4001704}}</ref> |- | [[FOXP2]] || 7q31 || The FOXP2 gene is of interest because it is known to be associated with developmental language and speech deficits. An association to autism appears to be elusive, nonetheless.<ref>{{cite journal |author=Marui T, Koishi S, Funatogawa I, ''et al'' |title=No association of FOXP2 and PTPRZ1 on 7q31 with autism from the Japanese population |journal=Neurosci. Res. |volume=53 |issue=1 |pages=91–4 |year=2005 |pmid=15998549 |doi=10.1016/j.neures.2005.05.003}}</ref><ref>{{cite journal |author=Gauthier J, Joober R, Mottron L, ''et al'' |title=Mutation screening of FOXP2 in individuals diagnosed with autistic disorder |journal=Am. J. Med. Genet. A |volume=118 |issue=2 |pages=172–5 |year=2003 |pmid=12655497 |doi=10.1002/ajmg.a.10105}}</ref> |- | [[UBE3A]] || 15q11-q13 || The UBE3A gene has been associated with [[Angelman syndrome]]. Samaco et al (2005) suggest reduced expression of UBE3A in autism, as is the case in [[Rett syndrome]].<ref>{{cite journal |author=Samaco RC, Hogart A, LaSalle JM |title=Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3 |journal=Hum. Mol. Genet. |volume=14 |issue=4 |pages=483–92 |year=2005 |pmid=15615769 |doi=10.1093/hmg/ddi045}}</ref> In any case, it appears that the role of UBE3A is limited. |- | [[Shank3]] (ProSAP2) || 22q13 || The gene called [[SHANK3]] (also designated ProSAP2) regulates the structural organization of neurotransmitter receptors in post-synaptic [[dendritic spines]] making it a key element in chemical binding crucial to nerve cell communication.<ref>{{cite journal |author=Schuetz G, Rosário M, Grimm J, Boeckers TM, Gundelfinger ED, Birchmeier W |title=The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells |journal=J. Cell Biol. |volume=167 |issue=5 |pages=945–52 |year=2004 |pmid=15569713 |doi=10.1083/jcb.200404108|url=http://www.jcb.org/cgi/content/full/167/5/945}}</ref> SHANK3 is also a binding partner of chromosome [[22q13]] (i.e. a specific section of Chromosome 22) and [[neuroligin]] proteins; deletions and mutations of SHANK3, [[22q13]] (i.e. a specific section of Chromosome 22) and genes encoding neuroligins have been found in some people with autism spectrum disorders.<ref name="orpha">[http://www.orpha.net/data/patho/GB/uk-22q13.pdf Deletion 22q13 Syndrome] M.C Phelan (2003) Orphanet.com</ref> Mutations in the SHANK3 gene have been strongly associated with the autism spectrum disorders. If the SHANK3 gene is not adequately passed to a child from the parent ([[haploinsufficiency]]) there will possibly be significant neurological changes that are associated with yet another gene, 22q13, which interacts with SHANK3. Alteration or deletion of either will effect changes in the other.<ref name="orpha"/> A deletion of a single copy of a gene on [[Chromosome 22 (human)|chromosome 22q13]] has been correlated with global developmental delay, severely delayed speech or social communication disorders and moderate to profound delay of cognitive abilities. Behavior is described as "autistic-like" and includes high tolerance to pain and habitual chewing or mouthing<ref name="orpha"/> (see also [[22q13 deletion syndrome]]). This appears to be connected to the fact that signal transmission between nerve cells is altered with the absence of 22q13. SHANK3 proteins also interact with neuroligins at the synapses of the brain further complicating the widespread effects of changes at the genetic level and beyond.<ref name="SHANK3">{{cite journal |author=Durand CM, Betancur C, Boeckers TM, ''et al'' |title=Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders |journal=Nat. Genet. |volume=39 |issue=1 |pages=25–7 |year=2007 |pmid=17173049 |doi=10.1038/ng1933|laysummary=http://www.autismspeaks.org/science/science_news/shank3_mutations.php|laysource= [[Autism Speaks]]|accessdate=2007-11-07}}</ref> |- | [[NLGN3]] || Xq13 || Neuroligin is a cell surface [[protein]] (homologous to [[acetylcholinesterase]] and other [[esterases]]) that binds to [[synaptic membranes]].<ref>[http://synapse-web.org/lab/harris/Lecture10-11/sld069.htm Neuroligins] Kristen Harris (2001) Cell adhesion at synapses Synapse Web, Laboratory of Synapse Structure and Function. Human Brain Project. National Institute of Mental Health and the National Institute of Drug Abuse</ref> Neuroligins organize postsynaptic membranes that function to transmit nerve cell messages (excitatory) and stop those transmissions (inhibitory);<ref> {{cite journal |author=Graf ER, Zhang X, Jin SX, Linhoff MW, Craig AM |title=Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins |journal=Cell |volume=119 |issue=7 |pages=1013–26 |year=2004 |pmid=15620359 |doi=10.1016/j.cell.2004.11.035}}</ref> In this way, neuroligins help to ensure signal transitions between nerve cells. Neuroligins are also regulate the maturation of synapses and ensure there are sufficient receptor proteins on the synaptic membrane. Mice with a neuroligin-3 mutation exhibit poor social skills but increased intelligence.<ref>{{cite journal |journal= Science |year=2007 |volume=318 |issue=5847 |pages=71–6 |title= A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice |author= Tabuchi K, Blundell J, Etherton MR ''et al.'' |doi=10.1126/science.1146221 |pmid=17823315|laysummary=http://www.sciencedaily.com/releases/2007/09/070907120758.htm |laydate=2007-09-08 |laysource= Science Daily}}</ref> Though not present in all individuals with autism, these mutations hold potential to illustrate some of the genetic components of spectrum disorders.<ref name="SHANK3"/> However, a 2008 study found no evidence for involvement of neuroligin-3 and neuroligin-4x with high-functioning ASD.<ref>{{cite journal |journal= Am J Med Genet B Neuropsychiatr Genet |date=2008 |title= No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level |author= Wermter AK, Kamp-Becker I, Strauch K, Schulte-Körne G, Remschmidt H |doi=10.1002/ajmg.b.30618 |pmid=18189281 |volume=147B |issue=4 |pages=535–7}}</ref> |- | [[C-Met|MET]] || 7q31 || The MET gene (MET receptor [[tyrosine kinase]] [[gene]]) linked to [[brain]] development, regulation of the [[immune system]], and repair of the [[gastrointestinal system]], has been linked to autism. This MET gene codes for a [[protein]] that relays signals that turn on a cell’s internal machinery. Impairing the receptor’s signaling interferes with [[neuron]] migration and disrupts neuronal growth in the [[cerebral cortex]] and similarly shrinks the [[cerebellum]]—abnormalities also seen in autism.<ref name="MET">[http://www.nih.gov/news/pr/oct2006/nimh-17.htm Gene Linked to Autism in Families with More Than One Affected Child] National Institutes of Health News (2006) Retrieved [[March 3]], [[2007]]</ref> It is also known to play a key role in both normal and abnormal development, such as [[cancer]] [[metastases]] (hence the name MET). A mutation of the gene, rendering it less active, has been found to be common amongst children with autism.<ref name="MET"/> Mutation in the MET gene demonstrably raises risk of autism by 2.27 times.<ref>{{cite journal |author=Campbell DB, Sutcliffe JS, Ebert PJ, ''et al'' |title=A genetic variant that disrupts MET transcription is associated with autism |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=45 |pages=16834–9 |year=2006 |pmid=17053076 |doi=10.1073/pnas.0605296103|laysummary=http://news.bbc.co.uk/2/hi/health/6055176.stm|laysource = BBC News|laydate =2006-10-28}}</ref> |- | [[neurexin 1]] || 2q32 || In February 2007, researchers in the Autism Genome Project (an international research team composed of 137 scientists in 50 institutions) reported possible implications in aberrations of a brain-development gene called neurexin 1 as a cause of some cases of autism.<ref name=AGPC2007>{{cite journal |journal= Nat Genet |date=2007 |volume=39 |issue=3 |pages=319–28 |title= Mapping autism risk loci using genetic linkage and chromosomal rearrangements |author= Autism Genome Project Consortium |doi=10.1038/ng1985 |pmid=17322880 |laysummary=http://www.yale.edu/opa/newsr/07-02-22-02.all.html |laysource=Yale |laydate=2007-02-18}} Corrigendum (2007). ''Nat Genet'' '''39''' (10): 1285. {{doi|10.1038/ng1007-1285a}}. PMID 17898782.</ref> Linkage analysis was performed on [[DNA]] from 1,181 families in what was the largest-scale genome scan conducted in autism research at the time. The objective of the study was to locate specific brain cells involved in autism to find regions in the [[genome]] linked to autism susceptibility [[genes]]. The focus of the research was [[copy number variation]]s (CNVs), extra or missing parts of genes. Each person does not actually have just an exact copy of genes from each parent. Each person also has occasional multiple copies of one or more genes or some genes are missing altogether. The research team attempted to locate CNVs when they scanned the DNA. Neurexin 1 is one of the genes that may be involved in communication between nerve cells ([[neurons]]). Neurexin 1 and other genes like it are very important in determining how the brain is connected from cell to cell, and in the chemical transmission of information between nerve cells. These genes are particularly active very early in brain development, either in utero or in the first months or couple of years of life. In some families their autistic child had only one copy of the neurexin 1 gene. Besides actually locating yet another possible genetic influence (the findings were statistically insignificant), the research also reinforced the theory that autism involves many forms of genetic variations. A 2008 study implicated the neurexin 1 gene in two independent subjects with ASD, and suggested that subtle changes to the gene might contribute to susceptibility to ASD.<ref>{{cite journal |journal= Am J Hum Genet |date=2008 |volume=82 |issue=1 |pages=199–207 |title= Disruption of neurexin 1 associated with autism spectrum disorder |author= Kim HG, Kishikawa S, Higgins AW ''et al.'' |pmid=18179900 |url=http://www.ajhg.org/AJHG/fulltext/S0002-9297(07)00017-1 |doi= 10.1016/j.ajhg.2007.09.011}}</ref> |- | [[CNTNAP2]] || 7q35-q36 || Multiple 2008 studies have identified a series of functional variants in the [[CNTNAP2]] gene, a member of the neurexin superfamily, that implicate it as contributing to autism.<ref>{{cite journal |journal= Am J Hum Genet |date=2008 |volume=82 |issue=1 |pages=150–9 |title= Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene |author= Alarcón M, Abrahams BS, Stone JL ''et al.'' |pmid=18179893 |url=http://www.ajhg.org/AJHG/fulltext/S0002-9297(07)00011-0 |laysummary=http://newsroom.ucla.edu/portal/ucla/ucla-scientists-identify-new-genetic-42778.aspx |laysource=UCLA Newsroom |laydate=2008-01-10 |doi= 10.1016/j.ajhg.2007.09.005}}</ref><ref>{{cite journal |journal= Am J Hum Genet |date=2008 |volume=82 |issue=1 |pages=160–4 |title= A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism |author= Arking DE, Cutler DJ, Brune CW ''et al.'' |pmid=18179894 |url=http://www.ajhg.org/AJHG/fulltext/S0002-9297(07)00021-3 |laysummary=http://www.hopkinsmedicine.org/Press_releases/2008/01_22_08.html |laydate=2008-01-22 |laysource= Johns Hopkins Medicine |doi= 10.1016/j.ajhg.2007.09.015}}</ref><ref>{{cite journal |journal= Am J Hum Genet |date=2008 |volume=82 |issue=1 |pages=165–73 |title= Molecular cytogenetic analysis and resequencing of Contactin Associated Protein-Like 2 in autism spectrum disorders |author= Bakkaloglu B, O'Roak BJ, Louvi A ''et al.'' |pmid=18179895 |url=http://www.ajhg.org/AJHG/fulltext/S0002-9297(07)00023-7 |doi= 10.1016/j.ajhg.2007.09.017}}</ref> |- | [[GSTP1]] || 11q13 || A 2007 study suggested that the GSTP1*A haplotype of the [[glutathione]] S-[[transferase]] P1 gene ([[GSTP1]]) acts in the mother during pregnancy and increases the likelihood of autism in the child.<ref>{{cite journal |author=Williams TA, Mars AE, Buyske SG, ''et al'' |title=Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype |journal=Archives of pediatrics & adolescent medicine |volume=161 |issue=4 |pages=356–61 |year=2007 |pmid=17404132 |doi=10.1001/archpedi.161.4.356|url=http://archpedi.ama-assn.org/cgi/content/full/161/4/356}}</ref> |- | [[PRL]], [[PRLR]], [[OXTR]] || multiple || A 2008 study found preliminary data supporting the hypothesis that ASD is associated with allelic variants of genes needed for typical [[affiliative behavior]]s. The strongest results were obtained for the PRL, PRLR, and [[OXTR]] genes.<ref>{{cite journal |journal= Biol Psychiatry |date=2008 |title= Genes controlling affiliative behavior as candidate genes for autism |author= Yrigollen CM, Han SS, Kochetkova A ''et al.'' |pmid=18207134}}</ref> |} ===Others=== There is a large number of other candidate [[locus|loci]] which either should be looked at or have been shown to be promising. Several [[genome]]-wide scans have been performed identifying markers across many [[chromosome]]s.<ref name=PMID16288458>{{cite journal |author=Ylisaukko-oja T, Alarcón M, Cantor RM, ''et al'' |title=Search for autism loci by combined analysis of Autism Genetic Resource Exchange and Finnish families |journal=Ann. Neurol. |volume=59 |issue=1 |pages=145–55 |year=2006 |pmid=16288458 |doi=10.1002/ana.20722}}</ref><ref>{{cite journal |author=Lauritsen MB, Als TD, Dahl HA, ''et al'' |title=A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands |journal=Mol. Psychiatry |volume=11 |issue=1 |pages=37–46 |year=2006 |pmid=16205737 |doi=10.1038/sj.mp.4001754}}</ref><ref>{{cite journal |author=Trikalinos TA, Karvouni A, Zintzaras E, ''et al'' |title=A heterogeneity-based genome search meta-analysis for autism-spectrum disorders |journal=Mol. Psychiatry |volume=11 |issue=1 |pages=29–36 |year=2006 |pmid=16189507 |doi=10.1038/sj.mp.4001750}}</ref> A few examples of loci that have been studied are the 17q21 region <ref name=PMID13680528>{{cite journal |author=Yonan AL, Alarcón M, Cheng R, ''et al'' |title=A genomewide screen of 345 families for autism-susceptibility loci |journal=Am J Hum Genet |volume=73 |issue=4 |pages=886-897 |year=2003 |pmid=13680528 |doi=}}</ref><ref name=PMID15877280>{{cite journal |author=Cantor RM, Kono N, Duvall JA, ''et al'' |title=Replication of autism linkage: fine-mapping peak at 17q21 |journal= Am J Hum Genet |volume=76 |issue=6 |pages=1050-1056 |year=2005 |pmid=15877280 |doi=10.1086/430278}}</ref>, the 3p24-26 locus,<ref name=PMID16288458/> PTEN,<ref>{{cite journal |author=Butler MG, Dasouki MJ, Zhou XP, ''et al'' |title=Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations |journal=J. Med. Genet. |volume=42 |issue=4 |pages=318–21 |year=2005 |pmid=15805158 |doi=10.1136/jmg.2004.024646}}</ref> and 15q11-q13.<ref name=PMID12819446/> Homozygosity mapping in pedigrees with shared ancestry and autism incidence has recently implicated the following candidate genes: [[PCDH10]], DIA1 (formerly known as C3ORF58), NHE9, [[CNTN3]], [[SCN7A]], and [[RNF8]]. Several of these genes appeared to be targets of MEF2,<ref>{{cite journal |author= Morrow EM, Yoo S, Flavell SW ''et al.'' |title= Identifying autism loci and genes by tracing recent shared ancestry |journal=Science |volume=321 |issue=5886 |pages=218–23 |year=2008 |pmid=18621663 |doi=10.1126/science.1157657 |laysummary=http://www.timesonline.co.uk/tol/life_and_style/health/article4311466.ece |laysource= The Times |laydate=2008-07-11}}</ref> one of the transcription factors known to be regulated by neuronal activity <ref>{{cite journal |author= Flavell SW, Cowan CW, Kim T, ''et al.'' |title= Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number |journal=Science |volume=311 |issue=5763 |pages=1008–12 |year=2006 |pmid=16484497 |doi=10.1126/science.1122511}}</ref> and that itself has also recently been implicated as an autism-related disorder candidate gene.<ref>{{cite journal |author= Li H, Radford JC, Ragusa MJ, ''et al.'' |title= Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo |journal= Proc Natl Acad Sci USA |volume=105 |issue=27 |pages=9397–402 |year=2008 |pmid=18599437 |doi=10.1073/pnas.0802876105}}</ref> Other possible candidates include:{{Fact|date=February 2007}} * [[SLC6A2]] ([[Social phobia]]) * [[FMR1]] (Fragile-X) * 5-HT-1Dbeta (OCD) * 7q11.23 ([[William's syndrome]], language impairment) * 4q34-35, 5q35.2-35.3, 17q25 ([[Tourette syndrome]]) * 2q24.1-31.1 (Intelligence) * 6p25.3-22.3 (Verbal IQ) * 22q11.2 (Visio-Spatial IQ) == References == {{reflist|2}} == Further reading == * {{cite journal |journal= Nat Rev Genet |year=2008 |volume=9 |issue=5 |pages=341–55 |title= Advances in autism genetics: on the threshold of a new neurobiology |author= Abrahams BS, Geschwind DH |doi=10.1038/nrg2346 |pmid=18414403}} This is an extremely high-quality but highly-technical review of the state of the science as of early 2008. == External links == * [http://agre.org/ Autism Genetic Resource Exchange (AGRE)] - 'the world's first collaborative gene bank for autism' {{Pervasive developmental disorders}} [[Category:Autism]] [[Category:Medical genetics]] [[hr:Nasljednost autizma]]