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Two-marker association tests yield new disease associations for coronary artery disease and hypertension

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Abstract

It has been postulated that multiple-marker methods may have added ability, over single-marker methods, to detect genetic variants associated with disease. The Wellcome Trust Case Control Consortium (WTCCC) provided the first successful large genome-wide association studies (GWAS) which included single-marker association analyses for seven common complex diseases. Of those signals detected, only one was associated with coronary artery disease (CAD), and none were identified for hypertension (HTN). Our objective was to find additional genetic associations and pathways for cardiovascular disease by examining the WTCCC data for variants associated with CAD and HTN using two-marker testing methods. We applied two-marker association testing to the WTCCC dataset, which includes ~2,000 affected individuals with each disorder, and a shared pool of ~3,000 controls, all genotyped using Affymetrix GeneChip 500 K arrays. For CAD, we detected single nucleotide polymorphisms (SNP) pairs in three genes showing genome-wide significance: HFE2, STK32B, and DIPC2. The most notable SNP pairs in a non-protein-coding region were at 9p21, a known major CAD-associated region. For HTN, we detected SNP pairs in five genes: GPR39, XRCC4, MYO6, ZFAT, and MACROD2. Four further associated SNP pair regions were at least 70 kb from any known gene. We have shown that novel, multiple-marker, statistical methods can be of use in finding variants in GWAS. We describe many new, associated variants for both CAD and HTN and describe their known genetic mechanisms.

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Acknowledgments

This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/info/participants.shtml. The work was supported by the National Institutes of Health, grant numbers: HL074166 and HL086718 from the National Heart, Lung, Blood Institute, HG003054 from the National Human Genome Research Institute, and, RR03655 from the National Center for Research Resources. Funding for the original WTCCC project was provided by the Wellcome Trust under award 076113.

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Authors and Affiliations

  1. Department of Genetics, Center for Human Genetics, University Hospitals of Cleveland and Case Western Reserve University, 10524 Euclid Avenue, Cleveland, OH, USA

    Thomas P. Slavin

  2. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, 44106, USA

    Tao Feng, Audrey Schnell, Xiaofeng Zhu & Robert C. Elston

  3. Department of Mathematics, Heilongjiang University, Harbin, 150086, China

    Tao Feng

  4. Hawai’i Community Genetics, 1441 Kapi‘olani Blvd., Ste 1800, Honolulu, HI, 96814, USA

    Thomas P. Slavin

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  1. Thomas P. Slavin
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Correspondence to Thomas P. Slavin.

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Slavin, T.P., Feng, T., Schnell, A. et al. Two-marker association tests yield new disease associations for coronary artery disease and hypertension. Hum Genet 130, 725–733 (2011). https://doi.org/10.1007/s00439-011-1009-6

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  • DOI: https://doi.org/10.1007/s00439-011-1009-6

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