Neurogenomics with Application to Schizophrenia and Other Major Neuropsychiatric Diseases with Complex Heredity

Abstract

There is a pressing need for novel pharmaceutical interventions for the major neuropsychiatric diseases schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD), and autism spectrum disorder (ASD). The heritable component of these disorders provides an avenue for understanding disease mechanism leading to novel pharmaceutical interventions. Progress toward this understanding is described. Variations in the genome include single nucleotide polymorphisms (SNPs) generally but not always of small effect size. Only a small subset of SNPs are within protein coding sequences. Structural variants (SVs) including copy number repeats (CNVs) can have larger influence on phenotype. These genetic variations are queried for influence on diseases using genome-wide association studies (GWASs) to reveal a largely polygenic influence on disease. This consists of multiple small contributions from common polymorphisms. Mutations with large effect size, for example from protein coding changes or chromosomal structural variations, often include de novo mutations. These also influence neuropsychiatric disease. Importantly, the genetic findings cross current diagnostic boundaries. The genomic studies seek improved mechanistic understanding leading to improved diagnostic and clinical practice and importantly provision of a basis for discovery of novel pharmaceuticals. Efforts toward these goals are discussed.