Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits
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We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.
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Conditional analysis, with UK Biobank linkage disequilibrium as reference, identified independent variants within each genome-wide significant merged locus.
“A conditional analysis 59 was used to identify independently-segregating variants in each of the merged loci that was genome-wide significant, using the linkage disequilibrium structure of UK Biobank as a reference panel.”
From Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions (2019) · cites this paper as [59]
GCTA COJO conditional analysis indicates that TREM2 and three other loci (BIN1, ABCA7, and PTK2B/CLU) have multiple independent LOAD association signals.
“GCTA COJO27 conditional analysis of the genome-wide loci indicates that TREM2 and three other loci (BIN1, ABCA7, and PTK2B/CLU) have multiple independent LOAD association signals”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [27]
Approximate conditional analysis did not identify secondary signal in any locus reaching genome-wide significance.
“We performed approximate conditional analysis in each locus reaching genome-wide significance using Genome-wide Complex Trait Analysis27 (GCTA) but did not identify secondary signal in any locus.”
From GWAS identifies 14 loci for device-measured physical activity and sleep duration (2018) · cites this paper as [27]
Conditional analysis within the 136 loci found 10 additional independently associated SNPs, giving 146 independent lead SNPs in total.
“Within these 136 loci, multi-SNP-based conditional analysis (Yang et al., 2012) identified 10 additional SNPs with independent associations, resulting in a total of 146 independent lead SNPs”
From Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders (2019) · cites this paper as Yang et al., 2012
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- Authors
- Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Yang, J., DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Ferreira, T., Morris, A. P., Medland, S. E., Madden, P. A. F., Heath, A. C., Martin, N. G., Montgomery, G. W., Weedon, M. N., Loos, R. J., Frayling, T. M., McCarthy, M. I., Hirschhorn, J. N., Goddard, M. E., & Visscher, P. M.
- Affiliations
- QIMR Berghofer Medical Research Institute (AU)
- Centre for Human Genetics (GB)
- Washington University in St. Louis (US)
- University of Exeter (GB)
- Addenbrooke's Hospital (GB)
- Broad Institute (US)
- The University of Melbourne (AU)
- The University of Queensland (AU)
- Corresponding author
- Visscher, Peter M
- ORCID
- Venue
- Nature Genetics
- Published
- 2012-03-18
- Volume
- 44
- Issue
- 4
- Pages
- 369-375
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3593158
- OpenAlex
- W2152885121
- Cited by
- 1,712
- References
- 37
- Citations by year
- 2026: 144 · 2025: 168 · 2024: 230 · 2023: 186 · 2022: 172 · 2021: 159 · 2020: 124 · 2019: 127 · 2018: 104 · 2017: 92 · 2016: 61 · 2015: 43 · 2014: 42 · 2013: 44 · 2012: 16
- FWCI
- 27.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Site cant be reached (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Wellcome Trust (WT083270, 090532)
- U.S. Public Health Service (HHSN 268200625226C)
- National Institute on Alcohol Abuse and Alcoholism (AA-10248, K05AA017688, R01AA013321, AA13320, AA13321, AA-014041, R01AA013326, AA13326, R01AA013320, R01AA014041, R01AA007535)
- National Heart, Lung, and Blood Institute (HHSN268201 100012C, HHSN268201100007I, HHSN268201100007C, HHSN2682 01100008C, HH-SN-268201100006C, HHSN268201100011C, HHSN2682011-00005I, HHSN2682011-00009I, R01 HL-59367, HHSN268201100005C, HHSN268201100005G, HHSN268201100010C, HHSN268201100011I, R01HL087641, R01HL059367, HHSN26820 1100009C, HHSN2682011-00008I, R01HL086694)
- National Institute on Drug Abuse (R56DA012854, DA12854, R01DA012854)
- National Human Genome Research Institute (U01HG004402)
- National Center for Research Resources (UL1RR025005)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- GWAS summary statistics, linkage disequilibrium, height, body mass index, type 2 diabetes, heritability, complex traits, case-control data
- MeSH terms
- Algorithms, Body Height, Data Interpretation, Statistical, Diabetes Mellitus, Type 2, Genotype, Humans, Phenotype, Genetic Variation, Meta-Analysis as Topic, Linkage Disequilibrium, Genome, Human, Body Mass Index, Case-Control Studies, Polymorphism, Single Nucleotide, Cyclin-Dependent Kinase Inhibitor p15, Genome-Wide Association Study, Genetic Loci
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