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

Delilah Zabaneh,Robert Plomin,David Lubinski,Martha Putallaz,Mike B Miller,Matt Mcgue,Eva Krapohl,Michael A Simpson,William G Iacono,Gerome Breen

doi:10.1038/srep41182

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.

Highlights

Cases M F Controls M F populations[10]
After quality control (QC), we estimated the first 10 principal components using linkage disequilibrium (LD) pruned whole-genome common SNP genotype data from the exome chip to correct for potential population structure in the subsequent analysis that focused on the HLA region only
A lookup of the association for our top SNPs: rs444921 and rs389512 in the two replication samples and four other studies is in Supplementary Table S4, and a meta-analysis for the top SNP with these studies is illustrated in Supplementary Figure S1

Summary

Introduction

Cases M F Controls M F populations[10]. Whereas HLA class I and class II genes encode sets of structurally related, highly polymorphic transplantation antigens, the class III genes display a low to moderate degree of genetic variability. Two non-genome wide studies investigated the association between HLA-DRB1 genotypes and cognitive traits in elderly individuals. We investigate the association between variants in 200 genes across the Class I and II HLA region using a unique case-control design. Cases and controls were from European ancestry from the US We previously applied this design and sample to conduct a case-control genome-wide analysis of extremely high intelligence using putative functional and exonic variants on the Illumina Infinium HumanExome BeadChip[17]. We aimed to test the association between these variants and extremely high intelligence, comparing allele frequencies for cases consisting of individuals selected for extremely high intelligence scores and controls who were unselected for intelligence

Objectives

Methods

Results

Conclusion