Genome-scale neurogenetics: methodology and meaning

Abstract

Genetic analysis is currently offering glimpses into molecular mechanisms underlying such neuropsychiatric disorders as schizophrenia, bipolar disorder and autism. After years of frustration, success in identifying disease-associated DNA sequence variation has followed from new genomic technologies, new genome data resources, and global collaborations that could achieve the scale necessary to find the genes underlying highly polygenic disorders. Here we describe early results from genome-scale studies of large numbers of subjects and the emerging significance of these results for neurobiology.

Figure 1

Allele frequency represents a continuum in human populations, with cutoffs between `common' and `rare' being somewhat arbitrary. On the left we display the frequency of common variants (common polymorphisms) and the large range of frequencies of rare variants. On the right we display the methodologies used to detect these various types of variation depending. For rare variants, design is based not only on allele frequency but also on whether the variant is transmitted or de novo. Whole-genome sequencing is not depicted because it has not yet been broadly incorporated into published studies in psychiatric genetics.