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Genome-wide analysis of epistasis in body mass index using multiple human populations.

ABSTRACT: We surveyed gene-gene interactions (epistasis) in human body mass index (BMI) in four European populations (n<1200) via exhaustive pair-wise genome scans where interactions were computed as F ratios by testing a linear regression model fitting two single-nucleotide polymorphisms (SNPs) with interactions against the one without. Before the association tests, BMI was corrected for sex and age, normalised and adjusted for relatedness. Neither single SNPs nor SNP interactions were genome-wide significant in either cohort based on the consensus threshold (P=5.0E-08) and a Bonferroni corrected threshold (P=1.1E-12), respectively. Next we compared sub genome-wide significant SNP interactions (P<5.0E-08) across cohorts to identify common epistatic signals, where SNPs were annotated to genes to test for gene ontology (GO) enrichment. Among the epistatic genes contributing to the commonly enriched GO terms, 19 were shared across study cohorts of which 15 are previously published genome-wide association loci, including CDH13 (cadherin 13) associated with height and SORCS2 (sortilin-related VPS10 domain containing receptor 2) associated with circulating insulin-like growth factor 1 and binding protein 3. Interactions between the 19 shared epistatic genes and those involving BMI candidate loci (P<5.0E-08) were tested across cohorts and found eight replicated at the SNP level (P<0.05) in at least one cohort, which were further tested and showed limited replication in a separate European population (n>5000). We conclude that genome-wide analysis of epistasis in multiple populations is an effective approach to provide new insights into the genetic regulation of BMI but requires additional efforts to confirm the findings.

SUBMITTER: Wei WH

PROVIDER: S-EPMC3400731 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Genome-wide analysis of epistasis in body mass index using multiple human populations.

Wei Wen-Hua WH Hemani Gib G Gyenesei Attila A Vitart Veronique V Navarro Pau P Hayward Caroline C Cabrera Claudia P CP Huffman Jennifer E JE Knott Sara A SA Hicks Andrew A AA Rudan Igor I Pramstaller Peter P PP Wild Sarah H SH Wilson James F JF Campbell Harry H Hastie Nicholas D ND Wright Alan F AF Haley Chris S CS

European journal of human genetics : EJHG 20120215 8

We surveyed gene-gene interactions (epistasis) in human body mass index (BMI) in four European populations (n<1200) via exhaustive pair-wise genome scans where interactions were computed as F ratios by testing a linear regression model fitting two single-nucleotide polymorphisms (SNPs) with interactions against the one without. Before the association tests, BMI was corrected for sex and age, normalised and adjusted for relatedness. Neither single SNPs nor SNP interactions were genome-wide signif ...[more]

PMID: 22333899

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Project description:BackgroundIn a previous study, we found low persistence of linkage disequilibrium (LD) phase across breeding populations of Atlantic salmon. Accordingly, we observed no increase in accuracy from combining these populations for genomic prediction. In this study, we aimed to examine if the same were true for detection power in genome-wide association studies (GWAS), in terms of reduction in p-values, and if the precision of mapping quantitative trait loci (QTL) would improve from such analysis. Since individual records may not always be available, e.g. due to proprietorship or confidentiality, we also compared mega-analysis and meta-analysis. Mega-analysis needs access to all individual records, whereas meta-analysis utilizes parameters, such as p-values or allele substitution effects, from multiple studies or populations. Furthermore, different methods for determining the presence or absence of independent or secondary signals, such as conditional association analysis, approximate conditional and joint analysis (COJO), and the clumping approach, were assessed.ResultsMega-analysis resulted in increased detection power, in terms of reduction in p-values, and increased precision, compared to the within-population GWAS. Only one QTL was detected using conditional association analysis, both within populations and in mega-analysis, while the number of QTL detected with COJO and the clumping approach ranged from 1 to 19. The allele substitution effect and -log10p-values obtained from mega-analysis were highly correlated with the corresponding values from various meta-analysis methods. Compared to mega-analysis, a higher detection power and reduced precision were obtained with the meta-analysis methods.ConclusionsOur results show that combining multiple datasets or populations in a mega-analysis can increase detection power and mapping precision. With meta-analysis, a higher detection power was obtained compared to mega-analysis. However, care must be taken in the interpretation of the meta-analysis results from multiple populations because their test statistics might be inflated due to population structure or cryptic relatedness.

Dataset Information

Genome-wide analysis of epistasis in body mass index using multiple human populations.

Publications

Genome-wide analysis of epistasis in body mass index using multiple human populations.

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