Novel Methods for Improving Power in Psychiatric Genetics

• Activity Number: 265
• Type: Invited
• Date/Time: Tuesday, August 5, 2014 : 8:30 AM to 10:20 AM
• Sponsor: Mental Health Statistics Section
• Author(s): Wesley Kurt Thompson*+
• Companies: University of California, San Diego
• Keywords: local false discovery rate ; genome-wide association studies ; psychiatric genetics ; genomic annotation ; schizophrenia

Abstract

Most of the genetic architecture underlying susceptibility to schizophrenia (SCZ) is not yet identified. Utilizing the largest SCZ genome-wide association study (GWAS) ever (n=82,315), and leveraging genomic annotation enrichment, we applied our newly developed covariate-modulated local false discovery rate (cmfdr) to discover 675 unique loci with cmfdr of 0.05 or less. The improved statistical power of the cmfdr method over standard approaches was confirmed by a consistent increase in the number of replicating loci, across a range of empirical replication rates. A substantial proportion of the identified genes were involved in intracellular cascades known to integrate signaling across different transmitter systems, including iono- and metabotropic receptors (for glutamate, dopamine, serotonin, GABA, ACh, opioids, ATP), ion channels (Ca2+, K+, Na+, Cl-), ion pumps, and signaling cascades downstream of G-protein coupled receptors. The results demonstrate that leveraging genomic annotation enrichment using our novel cmfdr method can greatly improve the power of GWAS in psychiatric disease.