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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

Genome-wide combined linkage and association results from a omnibus, b LIQ, and c NIQ analyses. The PPLD (posterior probability of LD) represents the probability of allelic association with ASD due to LD for each SNP in turn, and utilizes both linkage information from the multiplex families and association information from the trios. The x-axis represents the physical map for chromosomes 1–23 (X); the y-axis is on the probability scale. An additional 151 markers from the pseudoautosomal region of X are not shown on the graph; none had PPLD exceeding the prior probability of LD
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Fig2: Genome-wide combined linkage and association results from a omnibus, b LIQ, and c NIQ analyses. The PPLD (posterior probability of LD) represents the probability of allelic association with ASD due to LD for each SNP in turn, and utilizes both linkage information from the multiplex families and association information from the trios. The x-axis represents the physical map for chromosomes 1–23 (X); the y-axis is on the probability scale. An additional 151 markers from the pseudoautosomal region of X are not shown on the graph; none had PPLD exceeding the prior probability of LD

Mentions: Figure 2a shows omnibus PPLD results. Against a very clean background, two modest peaks stand out. These occur at rs11603469 (11p15.2, PPLD = 26%) and rs10221112 (16q21, PPLD = 15%). In both cases, surrounding SNPs are also giving PPLDs elevated above the baseline (prior) probability of LD. On 11p15.2, rs11603469 is one of a small cluster of SNPs showing some LD evidence and overlapping the gene FAR1 (rs11603469 itself is 10 kb from the FAR1 start site); on 16q21 the SNP falls 351 kb from the nearest annotated gene (GOT2). A third, smaller, LD signal stands out on 4q31.23 (PPLD = 6% at rs7668351, which falls in BC031092). In each case, these SNPs fall directly under corresponding linkage peaks (Fig. 3). It is noteworthy that in each case, multiple data subsets (sites) support LD, but also, multiple sites give evidence against LD, and some are merely neutral. In situations where allelic effects may vary across strata, pooling data across strata will tend to wash out these types of signals.Fig. 2


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)

Genome-wide combined linkage and association results from a omnibus, b LIQ, and c NIQ analyses. The PPLD (posterior probability of LD) represents the probability of allelic association with ASD due to LD for each SNP in turn, and utilizes both linkage information from the multiplex families and association information from the trios. The x-axis represents the physical map for chromosomes 1–23 (X); the y-axis is on the probability scale. An additional 151 markers from the pseudoautosomal region of X are not shown on the graph; none had PPLD exceeding the prior probability of LD
© Copyright Policy
Related In: Results  -  Collection

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

Fig2: Genome-wide combined linkage and association results from a omnibus, b LIQ, and c NIQ analyses. The PPLD (posterior probability of LD) represents the probability of allelic association with ASD due to LD for each SNP in turn, and utilizes both linkage information from the multiplex families and association information from the trios. The x-axis represents the physical map for chromosomes 1–23 (X); the y-axis is on the probability scale. An additional 151 markers from the pseudoautosomal region of X are not shown on the graph; none had PPLD exceeding the prior probability of LD
Mentions: Figure 2a shows omnibus PPLD results. Against a very clean background, two modest peaks stand out. These occur at rs11603469 (11p15.2, PPLD = 26%) and rs10221112 (16q21, PPLD = 15%). In both cases, surrounding SNPs are also giving PPLDs elevated above the baseline (prior) probability of LD. On 11p15.2, rs11603469 is one of a small cluster of SNPs showing some LD evidence and overlapping the gene FAR1 (rs11603469 itself is 10 kb from the FAR1 start site); on 16q21 the SNP falls 351 kb from the nearest annotated gene (GOT2). A third, smaller, LD signal stands out on 4q31.23 (PPLD = 6% at rs7668351, which falls in BC031092). In each case, these SNPs fall directly under corresponding linkage peaks (Fig. 3). It is noteworthy that in each case, multiple data subsets (sites) support LD, but also, multiple sites give evidence against LD, and some are merely neutral. In situations where allelic effects may vary across strata, pooling data across strata will tend to wash out these types of signals.Fig. 2

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