- Heritability of autism
Autismhas a strong genetic basis, although the geneticsof autism is complex and it is unclear whether ASD is explained more by multigene interactions or by rare mutations with major effects. [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] 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. This may be an overestimate; new twin data and models with structural genetic variation are needed. 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 phenotypemight be as high as 30%,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] much higher than the risk in controls. Genetic linkageanalysis has been inconclusive; many association analyses have had inadequate power.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] For each autistic individual, mutations 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 developmentand function. [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] [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] 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 abnormalitiessuch as fragile X syndromeor 22q13 deletion syndrome. [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] [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]
The large number of autistic individuals with unaffected family members may result from
copy number variations (CNVs)—spontaneous alterations in the genetic material during meiosisthat delete or duplicate genetic material. Sporadic (non-inherited) cases have been examined to identify candidate 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. [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] 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,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] 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. [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] The Autism Genome Project database contains genetic linkageand CNV data that connect autism to genetic loci and suggest that every human chromosomemay be involved. It may be that using autism-related subphenotypes instead of the diagnosis of autism per se may be more useful in identifying susceptible loci. [cite journal |journal= Biol Psychiatry |volume=64 |issue=7 |pages=561–70 |year=2008 |title= Genome-wide linkage analyses of quantitative and categorical autism subphenotypes |author= Liu XQ, Paterson AD, Szatmari P; The Autism Genome Project Consortium |doi=10.1016/j.biopsych.2008.05.023 |pmid=18632090]
Twin studiesare a helpful tool in determining the heritabilityof disorders and human traits in general. They involve determining concordance of characteristics between identical ( monozygoticor MZ) twins and between fraternal ( dizygoticor 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
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.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] Anexample 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.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=]
Identical twin studies put autism's
heritabilityin a range between 0.36 and 0.957, with concordance for a broader phenotypeusually found at the higher end of the range.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 Psychiatria et neurologia Japonica |volume=103 |issue=1 |pages=64–75 |year=2001 |pmid=11383012 |doi=] 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 theheritability 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. [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=]
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.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=]
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.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=]
In a 1989 study,
Nordic countrieswere 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.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=] 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." [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=]
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. [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=]
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. [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=]
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. [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=]
Another 2004 study examined whether the characteristic symptoms of autism (impaired social interaction, communication deficits, and repetitive behaviors) show decreased variance of symptoms among
monozygotictwins 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." [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]
An English twin study in 2006 found high heritability for autistic traits in a large group of 3,400 pairs of twins. [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]
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. [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]
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.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]
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." [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=]
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 syndromeor PDDwas 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." [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]
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 variationfrom their parents.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]
Other family studies
A 1994 looked at the personalities of parents of autistic children, using parents of children with
Down's syndromeas controls. Using standardized tests it was found that parents of autistic children were "more aloof, untactful and unresponsive." [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=]
A 1997 study found higher rates of social and communication deficits and stereotyped behaviors in families with multiple-incidence autism. [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=] Autism was found to occur more often in families of physicists, engineers and scientists. [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.] Other studies have yielded similar results. [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.] [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.] ] Findings of this nature have led to the coinage of the term "geek syndrome". [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.]
A 2001 study of brothers and parents of autistic boys looked into the
phenotypein 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. [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=]
A study in 2005 showed a positive correlation between repetitive behaviors in autistic individuals and obsessive-compulsive behaviors in parents. [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] 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. [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]
A 2005 report examined the family psychiatric history of 58 subjects with
Asperger's syndrome(AS) diagnosed according to DSM-IVcriteria. Three (5%) had first-degree relatives with AS. Nine (19%) had a family history of schizophrenia. Thirty five (60%) had a family history of depression. Out of 64 siblings, 4 (6.25%) were diagnosed with AS. [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=]
It has been suggested that the twinning process itself is a risk factorin the development of autism, presumably due to perinatal factors. [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=] However, three large-scale epidemiological studies have refuted this idea. [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=] 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]
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
genotypeor 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
genotypemodel 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.
The original Mendelian model tried to explain observations using distinct genes existing in clearly dominant or recessive
alleles. That would imply a recessive "autism gene" inherited from each of the parents. This kind of model is clearly too simple: [ [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. ]
* 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
alleleat 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
*(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
chromosomesFact|date=February 2007 .
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 alleles 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) and the broader phenotype results of Bolton et al (1994) 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
alleles.Fact|date=February 2007 Data supports the multiple-locus hypothesis and also that a 3-loci model is the best fit. [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=] Risch et al (1999) found results most compatible with a large number of loci (>= 15). [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=]
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
mutationwith poor penetrancein 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.
epigeneticmodels of autism have been proposed. [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] 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. [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]
Genomic imprintingmodels have been proposed; one of their strengths is explaining the high male-to-female ratio in ASD. [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=] One hypothesis is that autism is in some sense diametrically opposite to schizophreniaand 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. [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]
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. [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] 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. All known
teratogens (agents that cause birth defects) related to the risk of autism appear to act during the first eight weeks from conception, strong evidence that autism arises very early in development.cite journal |journal= Int J Dev Neurosci |date=2005 |volume=23 |issue=2–3 |pages=189–99 |title= The teratology of autism |author= Arndt TL, Stodgell CJ, Rodier PM |doi=10.1016/j.ijdevneu.2004.11.001 |pmid=15749245] Although evidence for other environmental causes is anecdotal and has not been confirmed by reliable studies, [cite journal |author= Rutter M |title= Incidence of autism spectrum disorders: changes over time and their meaning |journal= Acta Paediatr |volume=94 |issue=1 |date=2005 |pages=2–15 |pmid=15858952 |doi= 10.1080/08035250410023124] extensive searches are underway. [cite journal |journal= Environ Health Perspect |date=2006 |volume=114 |issue=7 |pages=A412–8 |title= Tracing the origins of autism: a spectrum of new studies |author= Szpir M |url=http://www.ehponline.org/members/2006/114-7/focus.html |pmid=16835042]
Candidate gene loci
A number of
alleles 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 genotypes that aremanifested 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.
There is a large number of other candidate 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 chromosomes.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] [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] [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]
A few examples of loci that have been studied are the 17q21 region 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=] 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] , the 3p24-26 locus, PTEN, [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] and 15q11.2–q13.
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, [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] [cite journal |journal=Nature |year=2008 |volume=454 |issue=7206 |pages=838–9 |title= Autism: Family connections |author= Geschwind DH |doi=10.1038/454838a |pmid=18704077] one of the transcription factors known to be regulated by neuronal activity [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] and that itself has also recently been implicated as an autism-related disorder candidate gene. [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]
Other possible candidates include:Fact|date=February 2007
SLC6A2( Social phobia)
* 5-HT-1Dbeta (OCD)
* 7q11.23 (
William's syndrome, language impairment)
* 4q34-35, 5q35.2-35.3, 17q25 (
* 2q24.1-31.1 (Intelligence)
* 6p25.3-22.3 (Verbal IQ)
* 22q11.2 (Visio-Spatial IQ)
* An excellent summary of the state and possible future directions of autism genetics research as of late 2007.
* Advocates common disease rare allele (CDRA) over polygenic approaches.
* Focuses on attempts to match genes to behavior.
* [http://agre.org/ Autism Genetic Resource Exchange (AGRE)] - 'the world's first collaborative gene bank for autism'
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