Detecting X-linked common and rare variant effects in family-based sequencing studies.

ABSTRACT

The breakthroughs in next generation sequencing have allowed us to access data consisting of both common and rare variants, and in particular to investigate the impact of rare genetic variation on complex diseases. Although rare genetic variants are thought to be important components in explaining genetic mechanisms of many diseases, discovering these variants remains challenging, and most studies are restricted to population-based designs. Further, despite the shift in the field of genome-wide association studies (GWAS) towards studying rare variants due to the "missing heritability" phenomenon, little is known about rare X-linked variants associated with complex diseases. For instance, there is evidence that X-linked genes are highly involved in brain development and cognition when compared with autosomal genes; however, like most GWAS for other complex traits, previous GWAS for mental diseases have provided poor resources to deal with identification of rare variant associations on X-chromosome. In this paper, we address the two issues described above by proposing a method that can be used to test X-linked variants using sequencing data on families. Our method is much more general than existing methods, as it can be applied to detect both common and rare variants, and is applicable to autosomes as well. Our simulation study shows that the method is efficient, and exhibits good operational characteristics. An application to the University of Miami Study on Genetics of Autism and Related Disorders also yielded encouraging results.