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Presence of multiple independent effects in risk loci of common complex human diseases.

ABSTRACT: Many genetic loci and SNPs associated with many common complex human diseases and traits are now identified. The total genetic variance explained by these loci for a trait or disease, however, has often been very small. Much of the "missing heritability" has been revealed to be hidden in the genome among the large number of variants with small effects. Several recent studies have reported the presence of multiple independent SNPs and genetic heterogeneity in trait-associated loci. It is therefore reasonable to speculate that such a phenomenon could be common among loci known to be associated with a complex trait or disease. For testing this hypothesis, a total of 117 loci known to be associated with rheumatoid arthritis (RA), Crohn disease (CD), type 1 diabetes (T1D), or type 2 diabetes (T2D) were selected. The presence of multiple independent effects was assessed in the case-control samples genotyped by the Wellcome Trust Case Control Consortium study and imputed with SNP genotype information from the HapMap Project and the 1000 Genomes Project. Eleven loci with evidence of multiple independent effects were identified in the study, and the number was expected to increase at larger sample sizes and improved statistical power. The variance explained by the multiple effects in a locus was much higher than the variance explained by the single reported SNP effect. The results thus significantly improve our understanding of the allelic structure of these individual disease-associated loci, as well as our knowledge of the general genetic mechanisms of common complex traits and diseases.

SUBMITTER: Ke X

PROVIDER: S-EPMC3397258 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Presence of multiple independent effects in risk loci of common complex human diseases.

Ke Xiayi X

American journal of human genetics 20120705 1

Many genetic loci and SNPs associated with many common complex human diseases and traits are now identified. The total genetic variance explained by these loci for a trait or disease, however, has often been very small. Much of the "missing heritability" has been revealed to be hidden in the genome among the large number of variants with small effects. Several recent studies have reported the presence of multiple independent SNPs and genetic heterogeneity in trait-associated loci. It is therefor ...[more]

PMID: 22770979

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Project description:Psoriasis is a common inflammatory skin disease characterized by thickened scaly red plaques. Previously we have performed a genome-wide association study (GWAS) on psoriasis with 1,359 cases and 1,400 controls, which were genotyped for 447,249 SNPs. The most significant finding was for SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw*0602, the consensus risk allele for psoriasis. However, it is not known whether there are other psoriasis loci within the MHC in addition to HLA-C. In the present study, we searched for additional susceptibility loci within the human leukocyte antigen (HLA) region through in-depth analyses of the GWAS data; then, we followed up our findings in an independent Han Chinese 1,139 psoriasis cases and 1,132 controls. Using the phased CEPH dataset as a reference, we imputed the HLA-Cw*0602 in all samples with high accuracy. The association of the imputed HLA-Cw*0602 dosage with disease was much stronger than that of the most significantly associated SNP, rs12191877. Adjusting for HLA-Cw*0602, there were two remaining association signals: one demonstrated by rs2073048 (p = 2 x 10(-6), OR = 0.66), located within c6orf10, a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p = 9 x 10(-6), OR = 1.3), located 30 kb centromeric of HLA-B and 16 kb telomeric of MICA. When HLA-Cw*0602, rs2073048, and rs13437088 were all included in a logistic regression model, each of them was significantly associated with disease (p = 3 x 10(-47), 6 x 10(-8), and 3 x 10(-7), respectively). Both putative loci were also significantly associated in the Han Chinese samples after controlling for the imputed HLA-Cw*0602. A detailed analysis of HLA-B in both populations demonstrated that HLA-B*57 was associated with an increased risk of psoriasis and HLA-B*40 a decreased risk, independently of HLA-Cw*0602 and the C6orf10 locus, suggesting the potential pathogenic involvement of HLA-B. These results demonstrate that there are at least two additional loci within the MHC conferring risk of psoriasis.

Dataset Information

Presence of multiple independent effects in risk loci of common complex human diseases.

Publications

Presence of multiple independent effects in risk loci of common complex human diseases.

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