Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases

Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium, SWE-SCZ Consortium

Research output: Contribution to journalArticle

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Abstract

Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg2) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg2 from imputed SNPs (5.1× enrichment; p = 3.7 × 10-17) and 38% (SE = 4%) of hg2 from genotyped SNPs (1.6× enrichment, p = 1.0 × 10 -4). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of hg2 despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.

Original languageEnglish
Pages (from-to)535-552
Number of pages18
JournalAmerican Journal of Human Genetics
Volume95
Issue number5
DOIs
Publication statusPublished - 2014
Externally publishedYes

Fingerprint

Single Nucleotide Polymorphism
Genome-Wide Association Study
Hypersensitivity
Exome
Linkage Disequilibrium
Schizophrenia
Genotype
Genome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium, & SWE-SCZ Consortium (2014). Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. American Journal of Human Genetics, 95(5), 535-552. https://doi.org/10.1016/j.ajhg.2014.10.004

Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. / Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium; Psychosis Endophenotypes International Consortium; Wellcome Trust Case Control Consortium; SWE-SCZ Consortium.

In: American Journal of Human Genetics, Vol. 95, No. 5, 2014, p. 535-552.

Research output: Contribution to journalArticle

Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium & SWE-SCZ Consortium 2014, 'Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases', American Journal of Human Genetics, vol. 95, no. 5, pp. 535-552. https://doi.org/10.1016/j.ajhg.2014.10.004
Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium, SWE-SCZ Consortium. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. American Journal of Human Genetics. 2014;95(5):535-552. https://doi.org/10.1016/j.ajhg.2014.10.004
Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium ; Psychosis Endophenotypes International Consortium ; Wellcome Trust Case Control Consortium ; SWE-SCZ Consortium. / Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. In: American Journal of Human Genetics. 2014 ; Vol. 95, No. 5. pp. 535-552.
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