On the Use of General Control Samples for Genome-wide Association Studies: Genetic Matching Highlights Causal Variants
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Resources being amassed for genome-wide association (GWA) studies include "control databases" genotyped with a large-scale SNP array. How to use these databases effectively is an open question. We develop a method to match, by genetic ancestry, controls to affected individuals (cases). The impact of this method, especially for heterogeneous human populations, is to reduce the false-positive rate, inflate other spuriously small p values, and have little impact on the p values associated with true positive loci. Thus, it highlights true positives by downplaying false positives. We perform a GWA by matching Americans with type 1 diabetes (T1D) to controls from Germany. Despite the complex study design, these analyses identify numerous loci known to confer risk for T1D.
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The method to analyze control and family-based data builds on two related ideas: matched case-control analysis using conditional logistic regression and the natural connection between family-based analysis and conditional logistic regression of alleles found in probands and matched pseudo-controls.
“The method to analyze control and family-based data (49) builds on two related ideas: matched case–control analysis using conditional logistic regression (e.g. 52) and the natural connection between family-based analysis and conditional logistic regression of alleles found in probands (the transmitted alleles) and matched pseudo-controls (formed from transmitted and un-transmitted alleles) (49).”
From A genome-wide scan for common alleles affecting risk for autism (2010) · cites this paper as [52]
Ancestry was inferred using clusterGem in GemTools, which found that five dimensions and seven clusters sufficiently described the ancestry space, and 667 subjects were assigned ancestry based on DNA genotypes.
“Ancestry was determined using clusterGem in GemTools (arXiv:1104.116260,61, http://www.wpic.pitt.edu/wpiccompgen/GemTools/GemTools.htm). Gemtools found that 5 dimensions and 7 clusters were sufficient to describe the ancestry space. Because one sample was missing key phenotypic information, 667 subjects were assigned ancestry based on DNA genotypes.”
From Gene expression elucidates functional impact of polygenic risk for schizophrenia (2016) · cites this paper as [61]
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- Authors
- Luca, D., Ringquist, S., Klei, L., Lee, A. B., Gieger, C., Wichmann, H.-E., Schreiber, S., Krawczak, M., Lu, Y., Styche, A., Devlin, B., Roeder, K., & Trucco, M.
- Affiliations
- Carnegie Mellon University (US)
- Children's Hospital of Pittsburgh (US)
- University of Pittsburgh (US)
- Helmholtz Munich (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Corresponding author
- Roeder, Kathryn
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 82
- Issue
- 2
- Pages
- 453-463
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2427172
- OpenAlex
- W2097902492
- Cited by
- 128
- References
- 42
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 13 · 2020: 2 · 2019: 7 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 5 · 2014: 2 · 2013: 9 · 2012: 8
- FWCI
- 12.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- Funders
- National Institutes of Health (MH057881)
- U.S. Department of Defense (W81XWH-07-1-0619)
- Juvenile Diabetes Research Foundation International
- George Washington University
- Joslin Diabetes Center
- Bundesministerium für Bildung und Forschung
- 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 › Forensic and Genetic Research
- Keywords
- genetic matching, control samples, genome-wide association study, type 1 diabetes, genetic ancestry, false positive rate, heterogeneous populations, causal variants
- MeSH terms
- Computer Simulation, Data Interpretation, Statistical, Diabetes Mellitus, Type 1, Genetics, Population, Germany, Humans, United States, Case-Control Studies, Polymorphism, Single Nucleotide, Genomics, Databases, Genetic, Control Groups, Inheritance Patterns
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