Dataset Information

Analysis of secondary phenotype involving the interactive effect of the secondary phenotype and genetic variants on the primary disease.

ABSTRACT: A genome-wide association (GWA) study is usually designed as a case-control study, where the presence and absence of the primary disease define the cases and controls, respectively. Using the existing data from GWA studies, investigators are also trying to identify the association between genetic variants and secondary phenotypes, which are defined as traits associated with the primary disease. However, recent studies have shown that bias arises in the estimation of marker-secondary phenotype association using originally collected data. We recently proposed a bias correction approach to accurately estimate the odds ratio (OR) for marker-secondary phenotype association. In this communication, we further investigated whether our bias correction approach is robust for a scenario involving the interactive effect of the secondary phenotype and genetic variants on the primary disease. We found that in such a scenario, our bias correction approach also provides an accurate estimation of OR for marker-secondary phenotype association. We investigated accuracy of our approach using simulation studies and showed that the approach better controlled for type I errors than the existing approaches. We also applied our bias correction approach to the real data analysis of association between an N-acetyltransferase gene, NAT2, and smoking on the basis of colorectal adenoma data.

SUBMITTER: Wang J

PROVIDER: S-EPMC3472120 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Analysis of secondary phenotype involving the interactive effect of the secondary phenotype and genetic variants on the primary disease.

Wang Jian J Shete Sanjay S

Annals of human genetics 20120810 6

A genome-wide association (GWA) study is usually designed as a case-control study, where the presence and absence of the primary disease define the cases and controls, respectively. Using the existing data from GWA studies, investigators are also trying to identify the association between genetic variants and secondary phenotypes, which are defined as traits associated with the primary disease. However, recent studies have shown that bias arises in the estimation of marker-secondary phenotype as ...[more]

PMID: 22881407

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Project description:Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.

Dataset Information

Analysis of secondary phenotype involving the interactive effect of the secondary phenotype and genetic variants on the primary disease.

Publications

Analysis of secondary phenotype involving the interactive effect of the secondary phenotype and genetic variants on the primary disease.

Similar Datasets

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