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Uncovering hidden variance: pair-wise SNP analysis accounts for additional variance in nicotine dependence

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Abstract

Results from genome-wide association studies of complex traits account for only a modest proportion of the trait variance predicted to be due to genetics. We hypothesize that joint analysis of polymorphisms may account for more variance. We evaluated this hypothesis on a case–control smoking phenotype by examining pairs of nicotinic receptor single-nucleotide polymorphisms (SNPs) using the Restricted Partition Method (RPM) on data from the Collaborative Genetic Study of Nicotine Dependence (COGEND). We found evidence of joint effects that increase explained variance. Four signals identified in COGEND were testable in independent American Cancer Society (ACS) data, and three of the four signals replicated. Our results highlight two important lessons: joint effects that increase the explained variance are not limited to loci displaying substantial main effects, and joint effects need not display a significant interaction term in a logistic regression model. These results suggest that the joint analyses of variants may indeed account for part of the genetic variance left unexplained by single SNP analyses. Methodologies that limit analyses of joint effects to variants that demonstrate association in single SNP analyses, or require a significant interaction term, will likely miss important joint effects.

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Acknowledgments

In memory of Theodore Reich, founding Principal Investigator of COGEND, we are indebted to his leadership in the establishment and nurturing of COGEND and acknowledge with great admiration his seminal scientific contributions to the field. Lead investigators directing data collection are Laura Bierut, Naomi Breslau, Dorothy Hatsukami, and Eric Johnson. The authors thank Heidi Kromrei and Tracey Richmond for their assistance in data collection and Brian Suarez for his thoughtful comments on the manuscript. This work was supported by National Institutes of Health grants K25 GM69590 from the National Institute of General Medical Sciences, R03 DA023166 from the National Institute on Drug Abuse (NIDA), and P01 CA89392 from the National Cancer Institute, as well as IRG-58-010-50 from the American Cancer Society. Genotyping services for this project were provided by Perlegen Sciences under NIDA Contract HHSN271200477471C. Additional genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096. Phenotypic and genotypic data are stored in the NIDA Center for Genetic Studies (NCGS) at http://zork.wustl.edu/ under NIDA Contract HHSN271200477451C (PIs J Tischfield and J Rice).

Conflict of interest

Drs. LJ Bierut, AM Goate, and JC Wang are listed as inventors on a patent “Markers for Addiction” (US 20070258898) covering the use of certain SNPs, including rs16969968, in determining the diagnosis, prognosis, and treatment of addiction. Dr. N Saccone is the spouse of S Saccone, who is also listed on the above patent. Dr. Bierut acted as a consultant for Pfizer, Inc. in 2008.

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Authors and Affiliations

  1. Division of General Medical Sciences, Department of Medicine, Washington University, Saint Louis, MO, 63110, USA

    Robert C. Culverhouse

  2. Division of Biostatistics, Washington University, Saint Louis, MO, 63110, USA

    Robert C. Culverhouse

  3. Department of Genetics, Washington University, Saint Louis, MO, 63110, USA

    Nancy L. Saccone, Alison M. Goate & Tae-Hwi Schwantes-An

  4. Department of Integrative Physiology, University of Colorado, Boulder, CO, 80309, USA

    Jerry A. Stitzel

  5. Department of Psychiatry, Washington University, Saint Louis, MO, 63110, USA

    Jen C. Wang, Alison M. Goate, Richard A. Grucza & Laura J. Bierut

  6. Department of Anesthesiology Basic Science Research, Washington University, Saint Louis, MO, 63110, USA

    Joseph H. Steinbach

  7. Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA, 30329, USA

    Victoria L. Stevens

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  1. Robert C. Culverhouse
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  2. Nancy L. Saccone
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  8. Richard A. Grucza
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  10. Laura J. Bierut
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Correspondence to Robert C. Culverhouse.

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Culverhouse, R.C., Saccone, N.L., Stitzel, J.A. et al. Uncovering hidden variance: pair-wise SNP analysis accounts for additional variance in nicotine dependence. Hum Genet 129, 177–188 (2011). https://doi.org/10.1007/s00439-010-0911-7

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