Emerging phenotyping strategies will advance our understanding of psychiatric genetics

Abstract

Over the last decade, genome-wide association studies (GWAS) of psychiatric disorders have identified numerous significant loci. Whereas these studies initially depended on cohorts ascertained for specific disorders, there has been a gradual shift in the ascertainment strategy towards population-based cohorts (PBCs) for which both genotype and heterogeneous phenotypic information are available. One of the advantages of PBCs is that, in addition to clinical diagnoses and various proxies for diagnoses ("minimal phenotyping"), many of them also provide non-clinical phenotypes, including putative endophenotypes, that can be used to study domains of normal function in addition to, or instead of, clinical diagnoses. By studying endophenotypes it is possible to both dissect psychiatric disorders ("splitting") and to combine multiple phenotypes ("clumping"), which can either reinforce or challenge traditional diagnostic categories. Such endophenotypes may also permit a deeper exploration of the neurobiology of psychiatric disorders. A coordinated effort to fully exploit the potential of endophenotypes is overdue.

Reviewing the genetics of heterogeneity in depression: operationalizations, manifestations and etiologies

“…Going beyond symptoms, recent expansions in sequencing and phenotyping technologies such as neuroimaging ( 88–90 ) and molecular data ( 91 , 92 ) have enabled genetic analyses on endophenotypes ( 93 ). Though genetic contributions to such endophenotypes have not yet been found to have larger individual locus effect sizes ( 94 ) or to be any less polygenic ( 95 ) than complex diseases, they have been proposed to be more tractable ( 96 ). Clustering based on endophenotypes may reveal etiologically meaningful subtypes of depression, and investigating these may allow us to fill in the missing causal links between genetic variants and disease.…”

Multivariate GWAS elucidates the genetic architecture of alcohol consumption and misuse, corrects biases, and reveals novel associations with disease

“…Analyzing alternative phenotypes as a complementary approach to studying clinically-defined AUD, and psychiatric disorders in general, has generated considerable interest in recent years (38).…”

Role of an Atypical Cadherin Gene,Cdh23in Prepulse Inhibition and Implication ofCDH23in Schizophrenia

“…2,3 With efforts to classify psychiatric disorders based on the dimensions of observable behavioral and neurobiological measures, endophenotype-based approaches for elucidating genetic liability have attracted interest because these approaches could mitigate clinical heterogeneity. 4,5 Among the behavioral endophenotypes, the prepulse inhibition (PPI) of acoustic startle response, a reflection of sensorimotor gating, has been consistently reported to be dampened in psychiatric disorders, particularly in schizophrenia. 6,7 As a robust and heritable endophenotype in schizophrenia, [8][9][10][11] the genes/variants conferring the risk of dampened PPI can help to elucidate the genetic architecture of schizophrenia.…”

“…2, 3 With efforts to classify psychiatric disorders based on the dimensions of observable behavioral and neurobiological measures, endophenotype-based approaches for elucidating genetic liability have attracted interest because these approaches could mitigate clinical heterogeneity. 4, 5…”