Abstract
Until very recently, few methods existed to analyze rare-variant association with binary phenotypes in complex pedigrees. We consider a set of recently proposed methods applied to the simulated and real hypertension phenotype as part of the Genetic Analysis Workshop 18. Minimal power of the methods is observed for genes containing variants with weak effects on the phenotype. Application of the methods to the real hypertension phenotype yielded no genes meeting a strict Bonferroni cutoff of significance. Some prior literature connects 3 of the 5 most associated genes (p <1 × 10−4) to hypertension or related phenotypes. Further methodological development is needed to extend these methods to handle covariates, and to explore more powerful test alternatives.
Highlights
The advent of next-generation sequencing technology has allowed researchers to actively consider the impact of rare genetic variation on common disease
NE, Dordt College, Sioux Center, IA 51250, USA Full list of author information is available at the end of the article it may be that separate, independent variations within the protein encoding region of a gene could alter protein structure and, explain phenotypic diversity. Many of these methods have shown limited utility to date. This limitation is the result of a host of factors, the most significant of which is the lack of power that results from testing extremely rare genetic variations in case-control samples
We found that use of the theoretical kinship matrix proved slightly overconservative, while using the estimated kinship matrix provided empirical type I error rates in line with the nominal levels
Summary
The advent of next-generation sequencing technology has allowed researchers to actively consider the impact of rare genetic variation on common disease. All of the recently proposed methods use the gene as the unit of analysis with the goal of aggregating independent genotype-phenotype association signals across the set of SNVs in the gene to boost statistical power versus the limited potential power from individually testing millions of SNVs, many of which may be extremely rare (eg, singletons). Many of these methods have shown limited utility to date This limitation is the result of a host of factors, the most significant of which is the lack of power that results from testing extremely rare genetic variations in case-control samples. Family-based study designs are increasingly being considered in an effort to potentially gain a better understanding of the role that rare genetic variation plays in explaining the heritability of common disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
