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Emerging phenotyping strategies will advance our understanding of psychiatric genetics

Abstract

Over the last decade, genome-wide association studies 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 toward population-based cohorts for which both genotype and heterogeneous phenotypic information are available. One of the advantages of population-based cohorts 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.

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Fig. 1: Case–control vs continuous phenotypes.
Fig. 2: The trade-off between phenotyping depth and sample size.
Fig. 3: Splitting vs clumping.

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Acknowledgements

S.S.R. was supported by the Frontiers of Innovation Scholars Program (#3-P3029), the Interdisciplinary Research Fellowship in NeuroAIDS (MH081482), a pilot award from the NIH (DA037844) and the 2018 NARSAD Young Investigator Grant (#27676). S.S.R. and A.A.P. were supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; #28IR-0070, and T29KT0526). A.A.P. was supported by NIH grants AA026281 and P50DA037844.

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Correspondence to Sandra Sanchez-Roige or Abraham A. Palmer.

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Sanchez-Roige, S., Palmer, A.A. Emerging phenotyping strategies will advance our understanding of psychiatric genetics. Nat Neurosci 23, 475–480 (2020). https://doi.org/10.1038/s41593-020-0609-7

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