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Novel method for combined linkage and genome-wide association analysis finds evidence of distinct genetic architecture for two subtypes of autism.

Vieland VJ, Hallmayer J, Huang Y, Pagnamenta AT, Pinto D, Khan H, Monaco AP, Paterson AD, Scherer SW, Sutcliffe JS, Szatmari P, Autism Genome Project (AG - J Neurodev Disord (2011)

Bottom Line: We found strong evidence of multiple linked loci; however, association evidence implicating specific genes was low even under the linkage peaks.Distinct loci were found in the lower IQ families, and these families showed stronger and more numerous linkage peaks, while the normal IQ group yielded the strongest association evidence.It appears that presence/absence of lower IQ (LIQ) demarcates more genetically homogeneous subgroups of ASD patients, with not just different sets of loci acting in the two groups, but possibly distinct genetic architecture between them, such that the LIQ group involves more major gene effects (amenable to linkage mapping), while the normal IQ group potentially involves more common alleles with lower penetrances.

View Article: PubMed Central - PubMed

Affiliation: Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital and The Ohio State University, Columbus, OH, 43205, USA, Veronica.Vieland@nationwidechildrens.org.

ABSTRACT
The Autism Genome Project has assembled two large datasets originally designed for linkage analysis and genome-wide association analysis, respectively: 1,069 multiplex families genotyped on the Affymetrix 10 K platform, and 1,129 autism trios genotyped on the Illumina 1 M platform. We set out to exploit this unique pair of resources by analyzing the combined data with a novel statistical method, based on the PPL statistical framework, simultaneously searching for linkage and association to loci involved in autism spectrum disorders (ASD). Our analysis also allowed for potential differences in genetic architecture for ASD in the presence or absence of lower IQ, an important clinical indicator of ASD subtypes. We found strong evidence of multiple linked loci; however, association evidence implicating specific genes was low even under the linkage peaks. Distinct loci were found in the lower IQ families, and these families showed stronger and more numerous linkage peaks, while the normal IQ group yielded the strongest association evidence. It appears that presence/absence of lower IQ (LIQ) demarcates more genetically homogeneous subgroups of ASD patients, with not just different sets of loci acting in the two groups, but possibly distinct genetic architecture between them, such that the LIQ group involves more major gene effects (amenable to linkage mapping), while the normal IQ group potentially involves more common alleles with lower penetrances. The possibility of distinct genetic architecture across subtypes of ASD has implications for further research and perhaps for research approaches to other complex disorders as well.

No MeSH data available.


Related in: MedlinePlus

PPL and PPLD for LIQ, NIQ groups respectively, for chromosomes a 3, b 8, c 11, d 16, e X containing SNPs shown in Table 1. Units on the x-axis are in cM
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Fig4: PPL and PPLD for LIQ, NIQ groups respectively, for chromosomes a 3, b 8, c 11, d 16, e X containing SNPs shown in Table 1. Units on the x-axis are in cM

Mentions: Table 1 shows all PPLDs ≥ 10% from the separate LIQ and NIQ analyses. Compared with the omnibus results, on 11p15.2, the omnibus signal in FAR1 is driven by the NIQ group (maximum PPLD = 32%). On 16q21, the omnibus signal is driven by the LIQ group, which on its own gives a PPLD = 7%, bolstered by a small signal from the MIQ group (not shown); none of these SNPs falls in an annotated gene. Some additional signals also appear in the subgroup analyses that were not salient in the omnibus results (see Fig. 4; this figure also shows the distinct genetic linkage patterns on chromosome 11). On 8q21.12 (LIQ, not in an annotated gene), a pair of SNPs is showing evidence of LD in a region not showing evidence of linkage (the second SNP, rs7007634, has PPLD = 8%). Additional association signals from the separate analyses are found on 3p12.1 (NIQ) and Xq13.1 (NIQ, with no clear difference between males and females) and 16p13.2 (LIQ).Table 1


Novel method for combined linkage and genome-wide association analysis finds evidence of distinct genetic architecture for two subtypes of autism.

Vieland VJ, Hallmayer J, Huang Y, Pagnamenta AT, Pinto D, Khan H, Monaco AP, Paterson AD, Scherer SW, Sutcliffe JS, Szatmari P, Autism Genome Project (AG - J Neurodev Disord (2011)

PPL and PPLD for LIQ, NIQ groups respectively, for chromosomes a 3, b 8, c 11, d 16, e X containing SNPs shown in Table 1. Units on the x-axis are in cM
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105232&req=5

Fig4: PPL and PPLD for LIQ, NIQ groups respectively, for chromosomes a 3, b 8, c 11, d 16, e X containing SNPs shown in Table 1. Units on the x-axis are in cM
Mentions: Table 1 shows all PPLDs ≥ 10% from the separate LIQ and NIQ analyses. Compared with the omnibus results, on 11p15.2, the omnibus signal in FAR1 is driven by the NIQ group (maximum PPLD = 32%). On 16q21, the omnibus signal is driven by the LIQ group, which on its own gives a PPLD = 7%, bolstered by a small signal from the MIQ group (not shown); none of these SNPs falls in an annotated gene. Some additional signals also appear in the subgroup analyses that were not salient in the omnibus results (see Fig. 4; this figure also shows the distinct genetic linkage patterns on chromosome 11). On 8q21.12 (LIQ, not in an annotated gene), a pair of SNPs is showing evidence of LD in a region not showing evidence of linkage (the second SNP, rs7007634, has PPLD = 8%). Additional association signals from the separate analyses are found on 3p12.1 (NIQ) and Xq13.1 (NIQ, with no clear difference between males and females) and 16p13.2 (LIQ).Table 1

Bottom Line: We found strong evidence of multiple linked loci; however, association evidence implicating specific genes was low even under the linkage peaks.Distinct loci were found in the lower IQ families, and these families showed stronger and more numerous linkage peaks, while the normal IQ group yielded the strongest association evidence.It appears that presence/absence of lower IQ (LIQ) demarcates more genetically homogeneous subgroups of ASD patients, with not just different sets of loci acting in the two groups, but possibly distinct genetic architecture between them, such that the LIQ group involves more major gene effects (amenable to linkage mapping), while the normal IQ group potentially involves more common alleles with lower penetrances.

View Article: PubMed Central - PubMed

Affiliation: Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital and The Ohio State University, Columbus, OH, 43205, USA, Veronica.Vieland@nationwidechildrens.org.

ABSTRACT
The Autism Genome Project has assembled two large datasets originally designed for linkage analysis and genome-wide association analysis, respectively: 1,069 multiplex families genotyped on the Affymetrix 10 K platform, and 1,129 autism trios genotyped on the Illumina 1 M platform. We set out to exploit this unique pair of resources by analyzing the combined data with a novel statistical method, based on the PPL statistical framework, simultaneously searching for linkage and association to loci involved in autism spectrum disorders (ASD). Our analysis also allowed for potential differences in genetic architecture for ASD in the presence or absence of lower IQ, an important clinical indicator of ASD subtypes. We found strong evidence of multiple linked loci; however, association evidence implicating specific genes was low even under the linkage peaks. Distinct loci were found in the lower IQ families, and these families showed stronger and more numerous linkage peaks, while the normal IQ group yielded the strongest association evidence. It appears that presence/absence of lower IQ (LIQ) demarcates more genetically homogeneous subgroups of ASD patients, with not just different sets of loci acting in the two groups, but possibly distinct genetic architecture between them, such that the LIQ group involves more major gene effects (amenable to linkage mapping), while the normal IQ group potentially involves more common alleles with lower penetrances. The possibility of distinct genetic architecture across subtypes of ASD has implications for further research and perhaps for research approaches to other complex disorders as well.

No MeSH data available.


Related in: MedlinePlus