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Wade, Michael J.

doi:10.1023/a:1013316611768

Cited by 69 publications

(8 citation statements)

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“…Searching only for main effects of loci and ignoring possible epistasis may reduce power to detect potentially causal variants (Cordell, 2002). In fact, some researchers have argued that the lack of replication across studies may be a hallmark of epistasis (Wade, 2001; Hirschhorn et al, 2002; Moore and Williams, 2002, 2005). Moreover, the detection of epistasis may help reveal potentially meaningful biological mechanisms (Risch, 1990), which is a central goal of translational research.…”

Section: Introductionmentioning

confidence: 99%

Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder

et al. 2013

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Genome-wide association studies (GWAS) have implicated ANK3 as a susceptibility gene for bipolar disorder (BP). We examined whether epistasis with ANK3 may contribute to the “missing heritability” in BP. We first identified via the STRING database 14 genes encoding proteins with prior biological evidence that they interact molecularly with ANK3. We then tested for statistical evidence of interactions between SNPs in these genes in association with BP in a discovery GWAS dataset and two replication GWAS datasets. The most significant interaction in the discovery GWAS was between SNPs in ANK3 and KCNQ2 (p = 3.18 × 10−8). A total of 31 pair-wise interactions involving combinations between two SNPs from KCNQ2 and 16 different SNPs in ANK3 were significant after permutation. Of these, 28 pair-wise interactions were significant in the first replication GWAS. None were significant in the second replication GWAS, but the two SNPs from KCNQ2 were found to significantly interact with five other SNPs in ANK3, suggesting possible allelic heterogeneity. KCNQ2 forms homo- and hetero-meric complexes with KCNQ3 that constitute voltage-gated potassium channels in neurons. ANK3 is an adaptor protein that, through its interaction with KCNQ2 and KCNQ3, directs the localization of this channel in the axon initial segment (AIS). At the AIS, the KCNQ2/3 complex gives rise to the M-current, which stabilizes the neuronal resting potential and inhibits repetitive firing of action potentials. Thus, these channels act as “dampening” components and prevent neuronal hyperactivity. The interactions between ANK3 and KCNQ2 merit further investigation, and if confirmed, may motivate a new line of research into a novel therapeutic target for BP.

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Section: Introductionmentioning

confidence: 99%

Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder

et al. 2013

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“…Overfitting happens when a complex model is fit to data and is not generalizable beyond the population from which the sample was derived [ 54 ]. The cause has commonly been attributed to either genetic or environmental heterogeneity [ 55 ], or due to epistasis [ 14 , 56 ].…”

Section: Methods To Identify Statistical Epistasis: Merits and Limmentioning

confidence: 99%

Bridging the Gap between Statistical and Biological Epistasis in Alzheimer’s Disease

Ebbert

Ridge

Kauwe

2015

BioMed Research International

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Alzheimer's disease affects millions of people worldwide and incidence is expected to rise as the population ages, but no effective therapies exist despite decades of research and more than 20 known disease markers. Research has shown that Alzheimer's disease's missing heritability remains extensive with an estimated 25% of phenotypic variance unexplained by known variants. The missing heritability may be explained by missing variants or by epistasis. Researchers often focus on individual loci rather than epistatic interactions, which is likely an oversimplification of the underlying biology since most phenotypes are affected by multiple genes. Focusing research efforts on epistasis will be critical to resolving Alzheimer's disease etiology, and a major key to identifying and properly interpreting key epistatic interactions will be bridging the gap between statistical and biological epistasis. This review covers the current state of epistasis research in Alzheimer's disease and how researchers can bridge the gap between statistical and biological epistasis to help resolve Alzheimer's disease etiology.

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“…Thus epistasis reflects basic interactive effects of mutations, genotypes, and/or their biological products [49].…”

Section: Pooling Strategymentioning

confidence: 99%

Identification of Genes for a Complex Trait: Examples from Hypertension

Binder

2006

CPB

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Essential hypertension (EH) affects approximately 20% of the adult population, and has a multifactorial origin arising from an interaction between susceptibility genes and environmental factors. Several strategies and methods have been used to identify hypertension susceptibility genes. This review is thought to highlight current strategies for a better understanding of their limitations and strengths in a complex trait like EH. Linkage analysis is less effective at identifying common variants with modest effects typical for complex traits, and has therefore proved to be largely unsuccessful in EH. No candidate gene was assessed by a human linkage study so far. Possible redesigns of the linkage approach for complex diseases may include larger sample sizes and dense marker maps. Genetic association studies may be an effective approach to the problems posed by complex traits. With the explosion of genotyping technologies, genome-wide association studies have become feasible, and small-scale association studies have become plentiful. The different types of association studies are reviewed and issues that are important to consider when interpreting association studies of complex traits are discussed. Properly defined phenotypes, large enough sample cohorts to achieve sufficient statistical power, carefully matched samples to avoid population stratification are all integral parts of a high-quality association study. Multiple testing often results in false-positive results by chance, and inconclusive results may arise from ignoring linkage disequilibrium of the tested polymorphism, an effect avoidable by haplotype analysis. A new evolutionary development of the candidate gene approach is introduced which will extent traditional association study settings gaining better understanding of complex diseases like hypertension and might give better chances to evaluate association studies for their functional relevance.

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Cited by 69 publications

References 0 publications

Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder

Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder

Bridging the Gap between Statistical and Biological Epistasis in Alzheimer’s Disease

Identification of Genes for a Complex Trait: Examples from Hypertension

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