Limits...
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 linkage analyses in a omnibus, b LIQ, c MIQ, and d NIQ groups. The PPL (posterior probability of linkage) represents the probability of an ASD gene at each position. The x-axis represents chromosomes 1–23 (X) on the Kosambi cM scale; the y-axis is on the probability scale. The horizontal line at PPL = 0.02 corresponds to the prior probability of linkage. Values below this line represent evidence against linkage, while values above the line represent evidence for linkage, at the given position
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Fig1: Genome-wide linkage analyses in a omnibus, b LIQ, c MIQ, and d NIQ groups. The PPL (posterior probability of linkage) represents the probability of an ASD gene at each position. The x-axis represents chromosomes 1–23 (X) on the Kosambi cM scale; the y-axis is on the probability scale. The horizontal line at PPL = 0.02 corresponds to the prior probability of linkage. Values below this line represent evidence against linkage, while values above the line represent evidence for linkage, at the given position

Mentions: Figure 1a shows genome-wide PPL results for the omnibus (all groups) analysis. 92.6% of the genome showed evidence against linkage, 97.4% of the genome had PPLs < 5%, and 98.7% of PPLs were <10% (99.6% ignoring chromosome 11, which shows several broad peaks). Against this backdrop, several peaks stand out. Two peaks on chromosome 11 coincide with locations reported in the two previous AGP analyses of this dataset (PPL = 60%@11p13; PPL = 93%@11p15.2). Also noteworthy is the very high PPL = 87% on 16q21, as well as several other peaks including: 2p25 (PPL = 12%), 4q31 (PPL = 33%), 6q14 (PPL = 11%), 18q22 (PPL = 18%), and possibly two additional peaks on 11p15 and 11q14, which are more moderate in size although still salient relative to the background. We note that the detection of multiple loci in this dataset is attributable largely to the PPL’s use of sequential updating. For instance, if we simply “pool” all sites and IQ groups together for a single analysis, on 16q21, the PPL at the peak is just 4%, compared to 87% based on sequential updating.Fig. 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)

Genome-wide linkage analyses in a omnibus, b LIQ, c MIQ, and d NIQ groups. The PPL (posterior probability of linkage) represents the probability of an ASD gene at each position. The x-axis represents chromosomes 1–23 (X) on the Kosambi cM scale; the y-axis is on the probability scale. The horizontal line at PPL = 0.02 corresponds to the prior probability of linkage. Values below this line represent evidence against linkage, while values above the line represent evidence for linkage, at the given position
© Copyright Policy
Related In: Results  -  Collection

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

Fig1: Genome-wide linkage analyses in a omnibus, b LIQ, c MIQ, and d NIQ groups. The PPL (posterior probability of linkage) represents the probability of an ASD gene at each position. The x-axis represents chromosomes 1–23 (X) on the Kosambi cM scale; the y-axis is on the probability scale. The horizontal line at PPL = 0.02 corresponds to the prior probability of linkage. Values below this line represent evidence against linkage, while values above the line represent evidence for linkage, at the given position
Mentions: Figure 1a shows genome-wide PPL results for the omnibus (all groups) analysis. 92.6% of the genome showed evidence against linkage, 97.4% of the genome had PPLs < 5%, and 98.7% of PPLs were <10% (99.6% ignoring chromosome 11, which shows several broad peaks). Against this backdrop, several peaks stand out. Two peaks on chromosome 11 coincide with locations reported in the two previous AGP analyses of this dataset (PPL = 60%@11p13; PPL = 93%@11p15.2). Also noteworthy is the very high PPL = 87% on 16q21, as well as several other peaks including: 2p25 (PPL = 12%), 4q31 (PPL = 33%), 6q14 (PPL = 11%), 18q22 (PPL = 18%), and possibly two additional peaks on 11p15 and 11q14, which are more moderate in size although still salient relative to the background. We note that the detection of multiple loci in this dataset is attributable largely to the PPL’s use of sequential updating. For instance, if we simply “pool” all sites and IQ groups together for a single analysis, on 16q21, the PPL at the peak is just 4%, compared to 87% based on sequential updating.Fig. 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