A scoping review and comparison of approaches for measuring genetic heterogeneity in psychiatric disorders

Abstract

An improved understanding of genetic etiological heterogeneity in a psychiatric condition may help us (a) isolate a neurophysiological 'final common pathway' by identifying its upstream genetic origins and (b) facilitate characterization of the condition's phenotypic variation. This review aims to identify existing genetic heterogeneity measurements in the psychiatric literature and provides a conceptual review of their mechanisms, limitations, and assumptions. The Scopus database was searched for studies that quantified genetic heterogeneity or correlation of psychiatric phenotypes with human genetic data. Ninety studies were included. Eighty-seven reports quantified genetic correlation, five applied genomic structural equation modelling, three evaluated departure from the Hardy-Weinberg equilibrium at one or more loci, and two applied a novel approach known as MiXeR. We found no study that rigorously measured genetic etiological heterogeneity across a large number of markers. Developing such approaches may help better characterize the biological diversity of psychopathology.

Lessons from ecology for understanding the heterogeneity of bipolar disorder

“…Still, distinct multivariate combinations of genetic risk variants may better characterize subgroups of these cohorts. 15 Novel analytical approaches, such as MiXeR, which attempt to quantify polygenic overlap beyond linear correlation, 13,16 may help us to identify distinct multivariate genetic profiles within the broad class of patients diagnosed with BD. Notwithstanding, phenotypic heterogeneity makes it difficult to infer the genetic architec ture of psychopathology based on GWAS data alone.…”