Haplotypes of common SNPs can explain missing heritability of complex diseases

BioRxiv : the Preprint Server for Biology
Gaurav Bhatia

Abstract

While genome-wide significant associations generally explain only a small proportion of the narrow-sense heritability of complex disease (h2), recent work has shown that more heritability is explained by all genotyped SNPs (hg2). However, much of the heritability is still missing (hg2 < h2). For example, for schizophrenia, h2 is estimated at 0.7-0.8 but hg2 is estimated at ~0.3. Efforts at increasing coverage through accurately imputed variants have yielded only small increases in the heritability explained, and poorly imputed variants can lead to assay artifacts for case-control traits. We propose to estimate the heritability explained by a set of haplotype variants (haploSNPs) constructed directly from the study sample (hhap2). Our method constructs a set of haplotypes from phased genotypes by extending shared haplotypes subject to the 4-gamete test. In a large schizophrenia data set (PGC2-SCZ), haploSNPs with MAF > 0.1% explained substantially more phenotypic variance (hhap2 = 0.64 (S.E. 0.084)) than genotyped SNPs alone (hg2 = 0.32 (S.E. 0.029)). These estimates were based on cross-cohort comparisons, ensuring that cohort-specific assay artifacts did not contribute to our estimates. In a large multiple sclerosis data set (W...Continue Reading

Related Concepts

Genome
Germ Cells
Multiple Sclerosis
Schizophrenia
Mass Spectrometry
Cohort
Strategy
Single Nucleotide Polymorphism
Position Sense Disorders
FGFR1 gene

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