Dataset Information

Fine mapping genetic associations between the HLA region and extremely high intelligence.

ABSTRACT: General cognitive ability (intelligence) is one of the most heritable behavioural traits and most predictive of socially important outcomes and health. We hypothesized that some of the missing heritability of IQ might lie hidden in the human leukocyte antigen (HLA) region, which plays a critical role in many diseases and traits but is not well tagged in conventional GWAS. Using a uniquely powered design, we investigated whether fine-mapping of the HLA region could narrow the missing heritability gap. Our case-control design included 1,393 cases with extremely high intelligence scores (top 0.0003 of the population equivalent to IQ?>?147) and 3,253 unselected population controls. We imputed variants in 200 genes across the HLA region, one SNP (rs444921) reached our criterion for study-wide significance. SNP-based heritability of the HLA variants was small and not significant (h2?=?0.3%, SE?=?0.2%). A polygenic score from the case-control genetic association analysis of SNPs in the HLA region did not significantly predict individual differences in intelligence in an independent unselected sample. We conclude that although genetic variation in the HLA region is important to the aetiology of many disorders, it does not appear to be hiding much of the missing heritability of intelligence.

SUBMITTER: Zabaneh D

PROVIDER: S-EPMC5259706 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Fine mapping genetic associations between the HLA region and extremely high intelligence.

Zabaneh Delilah D Krapohl Eva E Simpson Michael A MA Miller Mike B MB Iacono William G WG McGue Matt M Putallaz Martha M Lubinski David D Plomin Robert R Breen Gerome G

Scientific reports 20170124

General cognitive ability (intelligence) is one of the most heritable behavioural traits and most predictive of socially important outcomes and health. We hypothesized that some of the missing heritability of IQ might lie hidden in the human leukocyte antigen (HLA) region, which plays a critical role in many diseases and traits but is not well tagged in conventional GWAS. Using a uniquely powered design, we investigated whether fine-mapping of the HLA region could narrow the missing heritability ...[more]

PMID: 28117369

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Project description:In searching for genetic variants for complex diseases with deep sequencing data, genomic marker sets of high-dimensional genotypic data and sparse functional variants are quite common. Existing sequence association tests are incapable of identifying such marker sets or individual causal loci, although they appeared powerful to identify small marker sets with dense functional variants. In sequence association studies of admixed individuals, cryptic relatedness and population structure are known to confound the association analyses.We here propose a unified marker wise test (uFineMap) to accurately localize causal loci and a unified high-dimensional set based test (uHDSet) to identify high-dimensional sparse associations in deep sequencing genomic data of multi-ethnic individuals with random relatedness. These two novel tests are based on scaled sparse linear mixed regressions with Lp (0?<?p?<?1) norm regularization. They jointly adjust for cryptic relatedness, population structure and other confounders to prevent false discoveries and improve statistical power for identifying promising individual markers and marker sets that harbor functional genetic variants of a complex trait.With large scale simulation data and real data analyses, the proposed tests appropriately controlled Type I error rates and appeared to be more powerful than several prominent methods. We illustrated their practical utilities by the applications to DNA sequence data of Framingham Heart Study for osteoporosis. The proposed tests identified 11 novel significant genes that were missed by the prominent famSKAT and GEMMA. In particular, four out of six most significant pathways identified by the uHDSet but missed by famSKAT have been reported to be related to BMD or osteoporosis in the literature.The computational toolkit is available for academic use: https://sites.google.com/site/shaolongscode/home/uhdsetwyp@tulane.eduSupplementary data are available at Bioinformatics online.

Dataset Information

Fine mapping genetic associations between the HLA region and extremely high intelligence.

Publications

Fine mapping genetic associations between the HLA region and extremely high intelligence.

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