A Hybrid Likelihood Model for Sequence-Based Disease Association Studies

Abstract

In the past few years, case-control studies of common diseases have shifted their focus from single genes to whole exomes. New sequencing technologies now routinely detect hundreds of thousands of sequence variants in a single study, many of which are rare or even novel. The limitation of classical single-marker association analysis for rare variants has been a challenge in such studies. A new generation of statistical methods for case-control association studies has been developed to meet this challenge. A common approach to association analysis of rare variants is the burden-style collapsing methods to combine rare variant data within individuals across or within genes. Here, we propose a new hybrid likelihood model that combines a burden test with a test of the position distribution of variants. In extensive simulations and on empirical data from the Dallas Heart Study, the new model demonstrates consistently good power, in particular when applied to a gene set (e.g., multiple candidate genes with shared biological function or pathway), when rare variants cluster in key functional regions of a gene, and when protective variants are present. When applied to data from an ongoing sequencing study of bipolar disorder (191 cases, 107 controls), the model identifies seven gene sets with nominal p-values0.05, of which one MAPK signaling pathway (KEGG) reaches trend-level significance after correcting for multiple testing.

Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer

“…In addition to publicly available data from the 1000 Genomes Project and EVS, we compared our findings in the 87 selected genes to whole exome sequencing data from 967 unrelated participants of European ancestry from the Bipolar Case Control Study (BCCS) (30). In BCCS samples, call rates across the 87 genes averaged 0.889.…”

“…967 individuals were selected from the BCCS, also known as the Rare BLISS sample, to act as controls (30). DNA libraries were prepared by processing genomic DNA samples into Illumina paired-end libraries using Illumina compatible barcoded DNA adapters.…”

A sequence of methodological changes due to sequencing

“…Multiple different strategies have been employed, and these can be roughly grouped as variance-based test statistics [8,9 && ,10]; data-adaptive test statistics [11,12 & , [13][14][15][16][17][18][19]; optimal tests incorporating multiple test statistics [18][19][20]21 && , [22][23][24]; and Bayesian approaches [25][26][27][28] (Table 1) …”

Update on Research into the Genetics and Pharmacogenetics of Bipolar Disorder

“…The most significant pathway they found was MAPK signaling, in which genes coding for neuronal synapses were located, including CACNA1C (20).…”