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PMID: 24385918 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Quantifying missing heritability at known GWAS loci.

PLoS genetics ·Vol. 9 ·No. 12 ·2013-00-00 ·Pages e1003993

Gusev A, Bhatia G, Zaitlen N, Vilhjalmsson BJ, Diogo D, Stahl EA, Gregersen PK, Worthington J, Klareskog L, Raychaudhuri S, Plenge RM, Pasaniuc B, Price AL

Abstract

Recent work has shown that much of the missing heritability of complex traits can be resolved by estimates of heritability explained by all genotyped SNPs. However, it is currently unknown how much heritability is missing due to poor tagging or additional causal variants at known GWAS loci. Here, we use variance components to quantify the heritability explained by all SNPs at known GWAS loci in nine diseases from WTCCC1 and WTCCC2. After accounting for expectation, we observed all SNPs at known GWAS loci to explain 1.29 x more heritability than GWAS-associated SNPs on average (P=3.3 x 10⁻⁵). For some diseases, this increase was individually significant: 2.07 x for Multiple Sclerosis (MS) (P=6.5 x 10⁻⁹) and 1.48 x for Crohn's Disease (CD) (P = 1.3 x 10⁻³); all analyses of autoimmune diseases excluded the well-studied MHC region. Additionally, we found that GWAS loci from other related traits also explained significant heritability. The union of all autoimmune disease loci explained 7.15 x more MS heritability than known MS SNPs (P < 1.0 x 10⁻¹⁶ and 2.20 x more CD heritability than known CD SNPs (P = 6.1 x 10⁻⁹), with an analogous increase for all autoimmune diseases analyzed. We also observed significant increases in an analysis of > 20,000 Rheumatoid Arthritis (RA) samples typed on ImmunoChip, with 2.37 x more heritability from all SNPs at GWAS loci (P = 2.3 x 10⁻⁶) and 5.33 x more heritability from all autoimmune disease loci (P < 1 x 10⁻¹⁶ compared to known RA SNPs (including those identified in this cohort). Our methods adjust for LD between SNPs, which can bias standard estimates of heritability from SNPs even if all causal variants are typed. By comparing adjusted estimates, we hypothesize that the genome-wide distribution of causal variants is enriched for low-frequency alleles, but that causal variants at known GWAS loci are skewed towards common alleles. These findings have important ramifications for fine-mapping study design and our understanding of complex disease architecture.

MeSH Terms
Alleles Arthritis, Rheumatoid/genetics Crohn Disease/genetics Genetic Loci Genetic Predisposition to Disease Genome-Wide Association Study Humans Linkage Disequilibrium Models, Theoretical Multiple Sclerosis/genetics Polymorphism, Single Nucleotide
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Gusev Alexander
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America ; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America ; Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts, United States of America.
Bhatia Gaurav
Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts, United States of America ; Harvard-Massachusetts Institute of Technology (MIT) Division of Health, Science and Technology, Cambridge, Massachusetts, United States of America.
Zaitlen Noah
Department of Medicine Lung Biology Center, University of California San Francisco, San Francisco, California, United States of America.
Vilhjalmsson Bjarni J
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America ; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America ; Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts, United States of America.
Diogo Dorothée
Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts, United States of America ; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Stahl Eli A
Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts, United States of America ; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Gregersen Peter K
The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, United States of America.
Worthington Jane
Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
Klareskog Lars
Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
Raychaudhuri Soumya
Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts, United States of America ; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
Plenge Robert M
Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts, United States of America ; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Pasaniuc Bogdan
Department of Pathology and Laboratory Medicine, Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
Price Alkes L
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America ; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America ; Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts, United States of America.
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1003993
Published
2013-00-00
Epub
2013-00-26
Pages
e1003993
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC3873246
Subset
IM
Grants
NIGMS NIH HHS · F32 GM106584 · United States
NHGRI NIH HHS · U01 HG007033 · United States
NHGRI NIH HHS · R03HG006731 · United States
NIGMS NIH HHS · U01 GM092691 · United States
NHGRI NIH HHS · R03 HG006731 · United States
NIAMS NIH HHS · R01 AR063759 · United States
Wellcome Trust · United Kingdom
NIEHS NIH HHS · R21 ES020754 · United States
Arthritis Research UK · 20385 · United Kingdom
NIEHS NIH HHS · T32 ES007142 · United States
NIGMS NIH HHS · F32GM106584 · United States
External Links
PubMed source DOI: 10.1371/journal.pgen.1003993 PMC Full Text View journal details
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