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An examination of single nucleotide polymorphism selection prioritization strategies for tests of gene-gene interaction.

ABSTRACT: BACKGROUND:Given that genome-wide association studies (GWAS) of psychiatric disorders have identified only a small number of convincingly associated variants (single nucleotide polymorphism [SNP]), there is interest in seeking additional evidence for associated variants with tests of gene-gene interaction. Comprehensive pair-wise single SNP-SNP interaction analysis is computationally intensive, and the penalty for multiple testing is severe, given the number of interactions possible. Aiming to minimize these statistical and computational burdens, we have explored approaches to prioritize SNPs for interaction analyses. METHODS:Primary interaction analyses were performed with the Wellcome Trust Case-Control Consortium bipolar disorder GWAS (1868 cases, 2938 control subjects). Replication analyses were performed with the Genetic Association Information Network bipolar disorder dataset (1001 cases, 1033 control subjects). The SNPs were prioritized for interaction analysis that showed evidence for association that surpassed a number of nominally significant thresholds, are within genome-wide significant genes, or are within genes that are functionally related. RESULTS:For no set of prioritized SNPs did we obtain evidence to support the hypothesis that the selection strategy identified pairs of variants that were enriched for true (statistical) interactions. CONCLUSIONS:The SNPs prioritized according to a number of criteria do not have a raised prior probability for significant interaction that is detectable in samples of this size. We argue that the use of significance levels reflecting only the number of tests performed, as is now widely accepted for single SNP analysis, does not offer an appropriate degree of protection against the potential for GWAS studies to generate an enormous number of false positive interactions.

SUBMITTER: Moskvina V

PROVIDER: S-EPMC3125485 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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An examination of single nucleotide polymorphism selection prioritization strategies for tests of gene-gene interaction.

Moskvina Valentina V Craddock Nick N Müller-Myhsok Bertram B Kam-Thong Tony T Green Elaine E Holmans Peter P Owen Michael J MJ O'Donovan Michael C MC

Biological psychiatry 20110409 2

<h4>Background</h4>Given that genome-wide association studies (GWAS) of psychiatric disorders have identified only a small number of convincingly associated variants (single nucleotide polymorphism [SNP]), there is interest in seeking additional evidence for associated variants with tests of gene-gene interaction. Comprehensive pair-wise single SNP-SNP interaction analysis is computationally intensive, and the penalty for multiple testing is severe, given the number of interactions possible. Aim ...[more]

PMID: 21481336

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Project description:Dear Editor, The recent article by Mohammadzadeh et al.[1] on the latest issue of this Journal showed that the T allele +276G/T SNP of ADIPOQ gene is more associated with the increasing risk of coronary artery disease (CAD) in subjects with type 2 diabetes. Adipocytes were described in myocardial tissue of CAD patients and their role recently discussed[2,3]. Susceptibility to CAD by polymorphism in the Q gene of adiponectin has been reported for 3'-UTR, which harbours some genetic loci associated with metabolic risks and atherosclerosis[4]. Actually, previous studies have shown that the haplotype SNP +276G>T was associated with a decreased risk of CAD, after adjustment for potential confounding factors, therefore some controversial opinion still exists[5]. This evidence should be associated with the role exerted by adipocytes and adiponectin in heart physiology. In particular, in hypertensive disorder complicating pregnancy (HDCP), by investigating the population frequency of alleles, genotypes, and haplotypes of two single nucleotide polymorphisms (SNPs), namely +45T>G (rs2241766) and +276G>T (rs1501299), some authors found that the SNP +276 TT genotype was significantly associated with protection against HDCP, when compared to the pooled G genotypes[6]. Moreover, the same +276G/T SNP haplotype was strongly associated with biliary atresia, an intractable neonatal inflammatory and obliterative cholangiopathy, leading to progressive fibrosis and cirrhosis[7]. CAD is closely related to adiponectin biology. The same isoforms of adiponectin seem to be not associated to CAD severity but to glucose metabolism and its impairment[8]. In the paper by Mohammadzadeh et al.[1], T allele in +276G/T SNP haplotype is highly associated with CAD in subjects with type 2 diabetes, but this linkage should be reappraised if related much more to diabetes rather than CAD. Association of T allele in the indicated SNP with CAD may be an indirect consequence of type 2 diabetes, as reported by others[9] or a direct marker for CAD affected patients[10]. The paper by Mohammadzadeh et al.[1] assesses data coming elsewhere from literature but raises important concerns about the suitability of ADIPOQ SNPs in diagnosing susceptibility to CAD and the relationship with plasma adiponectin level. In normal, non diabetic, normoglycemic subject, this relationship does not seem to work. Therefore the question is how much predictive this SNP haplotype may be to foresee metabolic syndrome and CAD onset risk in young health subjects? Maybe, the role of adiponectin in cardiovascular physiology depends on its ability to target adiponectin receptors and to negatively regulate obesity. Some authors reported in healthy volunteers an absence of correlation between circulating adiponectin levels and biochemical markers, particularly lipoproteins and suggested that SNP +276G>T was related to an independent effect on adiponectin levels and on lipoprotein metabolism[11]. On the contrary, adiponectin genetic variants and SNP +276G>T was associated with increasing susceptibility of type 2 diabetes and plasma glucose impairment[12]. The interesting study by Mohammadzadeh et al.[1] suggests that SNP of ADIPOQ +276G>T should be related to susceptibility to glucose metabolism, while indirectly to lipid metabolism and fat-related cardiovascular damage.

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An examination of single nucleotide polymorphism selection prioritization strategies for tests of gene-gene interaction.

Publications

An examination of single nucleotide polymorphism selection prioritization strategies for tests of gene-gene interaction.

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