Evidence for Sex-Specific Risk Alleles in Autism Spectrum Disorder

Stone, Jennifer; Merriman, Barry; Cantor, Rita M.; Yonan, Amanda L.; Gilliam, T. Conrad; Geschwind, Daniel H.; Nelson, Stanley F.

doi:10.1086/426034

Cited by 161 publications

(146 citation statements)

References 19 publications

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“…The primary analysis was an affected sib-pair genome scan to detect autism loci using the diagnosis as the phenotype. Our secondary analyses attempted to replicate specific regional linkage signals reported by others who stratified their sample using gender, 20 developmental regression, 27 and language acquisition. 29 Our tertiary analyses explored the possibility of additional regions with relevant loci by completing the scan for the rest of the genome using strata defined by the same gender, developmental regression and language acquisition phenotypes.…”

Section: Resultsmentioning

confidence: 99%

“…Notably missing from our genome scan were signals corresponding to those reported by others on chromosome 2 13,16,17,23,45 and chromosome 17. 14,20,24 Gender and linkage analyses Previous work by others suggested that linkage signals on chromosomes 4, 14,20 7, 17 and 17 14,20 were dependent on the gender of the affected individuals in the families. To attempt to replicate these findings, we used the same stratification design, dividing our sample into families with only male affected individuals (MO families; 113 strict, 148 broad), and families with at least one affected female sib (FC families; 56 strict, 74 broad; Table S4).…”

Section: Primary Genome Scanmentioning

confidence: 99%

“…16,17,25 Likewise, we replicate a previously reported signal on chromosome 4 from FC sibships. 20 We obtained additional novel strong signals at the 9q terminal region using age at first word as a quantitative trait, chromosome 11 in MO sibships and chromosome 3 in regression-negative families. The fact that we were able to confirm signals from other studies strongly suggests that linkage analysis will lead to successful identification of at least some of the genes responsible for autism susceptibility.…”

Section: Introductionmentioning

confidence: 98%

“…To date, genomewide linkage studies of autism in eight largely nonoverlapping family collections have been published. [12][13][14][15][16][17][18][19][20][21][22][23][24][25] The number of families in these studies ranges from 39 12 to 345 24 families with most kindreds having two affected siblings. While no single region has been unambiguously associated with autism, coincident signals for specific chromosomal regions have been identified in multiple studies.…”

Section: Introductionmentioning

confidence: 99%

“…For our primary analysis, the trait used is the affectation status of family members. Based on recent findings by others, we also conducted secondary stratified and quantitative trait analyses of: (1) families with only male affected children (male-only, MO) versus families where there was at least one affected female child (female-containing, FC); 17,20 (2) families with or without developmental regression; 27 and (3) age at first word and phrase as quantitative traits. 13,[28][29][30] Our results provide strong evidence for an autism locus on chromosome 7q with the evidence for linkage being strongest in the subset with the strictest diagnosis.…”

Section: Introductionmentioning

confidence: 99%

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Evidence for multiple loci from a genome scan of autism kindreds

et al. 2006

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We performed a genome-wide linkage scan using highly polymorphic microsatellite markers. To minimize genetic heterogeneity, we focused on sibpairs meeting the strict diagnosis of autism. In our primary analyses, we observed a strong linkage signal (P = 0.0006, 133.16 cM) on chromosome 7q at a location coincident with other linkage studies. When a more relaxed diagnostic criteria was used, linkage evidence at this location was weaker (P = 0.01). The sample was stratified into families with only male affected subjects (MO) and families with at least one female affected subject (FC). The strongest signal unique to the MO group was on chromosome 11 (P = 0.0009, 83.82 cM), and for the FC group on chromosome 4 (P = 0.002, 111.41 cM). We also divided the sample into regression positive and regression negative families. The regression-positive group showed modest linkage signals on chromosomes 10 (P = 0.003, 0 cM) and 14 (P = 0.005, 104.2 cM). More significant peaks were seen in the regression negative group on chromosomes 3 (P = 0.0002, 140.06 cM) and 4 (P = 0.0005, 111.41 cM). Finally, we used language acquisition data as a quantitative trait in our linkage analysis and observed a chromosome 9 signal (149.01 cM) of P = 0.00006 and an empirical P-value of 0.0008 at the same location. Our work provides strong conformation for an autism locus on 7q and suggestive evidence for several other chromosomal locations. Diagnostic specificity and detailed analysis of the autism phenotype is critical for identifying autism loci.

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Section: Resultsmentioning

confidence: 99%

Section: Primary Genome Scanmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence for multiple loci from a genome scan of autism kindreds

et al. 2006

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Genetics of cognitive disorders

Abrahams

Geschwind

2005

Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics

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Disorders of cognition impair mental processes mediating awareness, perception, reasoning, or judgment, and consequently interfere with thought. Although interindividual differences in human cognition are easily observed, little is known about the genetic factors underlying such phenotypic variation, or the relationship of such variation to disease. Global measures of intelligence, such as Spearman's “g”, are heritable and thus likely to engender new links between genes and cognition. However, the breadth of these measures may limit the extent to which mechanistic insights are obtained. Finding readily measurable and heritable components of disease (endophenotypes) represents one of the most promising avenues for a precise understanding of how individual genes come to modulate brain function. The high heritability of interindividual differences in brain morphology suggests that a more thorough understanding of disease‐associated structural variation may clarify the relationship between individual genes and disorders of cognition. Identification and study of endophenotypes for autism and disorders of spoken and written language will facilitate a deeper understanding of how genetic variation comes to modulate the structure and function of particular neural systems and in turn contributes to specific cognitive deficits.

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Molecular Genetics of Autism

Lamb

2009

Encyclopedia of Life Sciences

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Autism is a behaviourally defined lifelong neurodevelopmental disorder, with strong evidence for a complex genetic predisposition. Extensive genetic research has been carried out over the last decade using cytogenetic, linkage and association approaches to identify the underlying risk variants, with generally equivocal results. The most exciting recent finding to emerge in autism genetics is the discovery of submicrosopic copy number variants and rare gene mutations that appear to increase the risk of autism. These findings suggest possible biological pathways involved, pointing to postsynaptic density genes and defective glutamatergic synaptogenesis. Some of these variants are also implicated in mental retardation and other neurodevelopmental and psychiatric disorders. Together, these findings suggest considerable genetic and clinical heterogeneity underlies autism spectrum disorders, and that convergent approaches may be required to identify risk alleles. Key concepts Autism is a behaviourally defined lifelong neurodevelopmental disorder, with strong evidence for a complex genetic predisposition. A large number of linkage and candidate gene association studies carried out over the last decade to identify risk variants have yielded generally equivocal results. Submicrosopic copy number variants and rare gene mutations have recently been discovered that appear to increase the risk of autism; the same variants may also influence mental retardation and other neurodevelopmental and psychiatric disorders. These findings implicate postsynaptic density genes and defective glutamatergic synaptogenesis in susceptibility to autism. There is increasing recognition that considerable genetic and clinical heterogeneity is likely to underlie autism spectrum disorders. Interdisciplinary, convergent approaches and large sample sizes may be required to identify the risk variants and biological pathways involved. Technologies are rapidly evolving together with knowledge of the human genome, providing greater ability to assay genetic variation.

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Evidence for Sex-Specific Risk Alleles in Autism Spectrum Disorder

Cited by 161 publications

References 19 publications

Evidence for multiple loci from a genome scan of autism kindreds

Evidence for multiple loci from a genome scan of autism kindreds

Genetics of cognitive disorders

Molecular Genetics of Autism

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