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Haplotypes of common SNPs can explain missing heritability of complex diseases

Gaurav Bhatia, Alexander Gusev, Po-Ru Loh, Bjarni J. Vilhjálmsson, Stephan Ripke, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Shaun Purcell, Eli Stahl, Mark Daly, Teresa R de Candia, Kenneth S. Kendler, Michael C O’Donovan, Sang Hong Lee, Naomi R. Wray, Benjamin M Neale, Matthew C. Keller, Noah A. Zaitlen, Bogdan Pasaniuc, Jian Yang, Alkes L. Price
doi: https://doi.org/10.1101/022418
Gaurav Bhatia
1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
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Alexander Gusev
1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
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Po-Ru Loh
1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
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Bjarni J. Vilhjálmsson
1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
3Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
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Stephan Ripke
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Shaun Purcell
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
5Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
6Department of Psychiatry, Mt. Sinai Hospital, NY, USA
7Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY, USA
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Eli Stahl
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
8Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
9Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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Mark Daly
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Teresa R de Candia
10Department of Psychology and Neuroscience, University of Colorado, Boulder, Boulder, CO, USA
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Kenneth S. Kendler
11Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA
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Michael C O’Donovan
12MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
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Sang Hong Lee
13Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
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Naomi R. Wray
13Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
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Benjamin M Neale
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Matthew C. Keller
14Institute for Behavioral Genetics, University of Colorado, Boulder, Boulder, CO, USA
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Noah A. Zaitlen
15Lung Biology Center, School of Medicine, University of California, San Francisco, San Francisco, CA, USA
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Bogdan Pasaniuc
16Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, USA
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Jian Yang
12MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
17The University of Queensland Diamantina Institute, The Translation Research Institute, Brisbane, Queensland, Australia
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Alkes L. Price
1Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
18Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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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 (WTCCC2-MS), we observed an even larger difference between hhap2 and hg2, though data from other cohorts will be required to validate this result. Overall, our results suggest that haplotypes of common SNPs can explain a large fraction of missing heritability of complex disease, shedding light on genetic architecture and informing disease mapping strategies.

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Posted July 12, 2015.
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Haplotypes of common SNPs can explain missing heritability of complex diseases
Gaurav Bhatia, Alexander Gusev, Po-Ru Loh, Bjarni J. Vilhjálmsson, Stephan Ripke, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Shaun Purcell, Eli Stahl, Mark Daly, Teresa R de Candia, Kenneth S. Kendler, Michael C O’Donovan, Sang Hong Lee, Naomi R. Wray, Benjamin M Neale, Matthew C. Keller, Noah A. Zaitlen, Bogdan Pasaniuc, Jian Yang, Alkes L. Price
bioRxiv 022418; doi: https://doi.org/10.1101/022418
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Haplotypes of common SNPs can explain missing heritability of complex diseases
Gaurav Bhatia, Alexander Gusev, Po-Ru Loh, Bjarni J. Vilhjálmsson, Stephan Ripke, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Shaun Purcell, Eli Stahl, Mark Daly, Teresa R de Candia, Kenneth S. Kendler, Michael C O’Donovan, Sang Hong Lee, Naomi R. Wray, Benjamin M Neale, Matthew C. Keller, Noah A. Zaitlen, Bogdan Pasaniuc, Jian Yang, Alkes L. Price
bioRxiv 022418; doi: https://doi.org/10.1101/022418

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