Leveraging Characteristics of Common Genetic Variants to Improve Power of Gene Discovery in Genome-wide Association Study of Neuroticism

Neuroticism reflects emotional instability, and is related to various mental and physical health issues. However, the majority of genetic variants associated with neuroticism remains unclear. Inconsistent genetic variants... [ view full abstract ]

Neuroticism reflects emotional instability, and is related to various mental and physical health issues. However, the majority of genetic variants associated with neuroticism remains unclear. Inconsistent genetic variants identified by different genome-wide association studies (GWAS) may be attributable to low statistical power. We proposed a novel framework to improve the power for gene discovery by incorporating single nucleotide polymorphism (SNP) characteristics and combining two relevant tools, relative enrichment score (RES) by Wang et al. and conditional false discovery rate (FDR) by Andreassen et al. Here, conditional FDR for each SNP was estimated given its RES based on linkage disequilibrium (LD)-weighted genic annotation scores, total LD scores, and heterozygosity. A known significant locus in chromosome 8p was excluded before estimating FDR due to long-range LD structure. Only one significant LD-independent SNP was detected by analyses of unconditional FDR and traditional GWAS in the discovery sample (N = 59,225), and notably four additional SNPs by conditional FDR. Three of the five SNPs, all identified by conditional FDR, were replicated in an independent sample (N = 170,911). These three SNPs are located in intronic regions of CADM2, LINGO2 and EP300 which have been reported to be associated with autism, Parkinson's disease, and schizophrenia, respectively. Our approach using a combination of RES and conditional FDR can improve power of traditional GWAS for gene discovery, which provides a useful framework for the analysis of GWAS summary statistics by utilizing SNP characteristics, and helps to elucidate the links between neuroticism and complex diseases from a genetic perspective.