Polygenic risk score, genome-wide association, and gene set analyses of cognitive domain deficits in schizophrenia

Soichiro Nakahara; Sarah Medland; Jessica A Turner; Vince D Calhoun; Kelvin O Lim; Bryon A Mueller; Juan R Bustillo; Daniel S O'Leary; Jatin G Vaidya; Sarah McEwen; James Voyvodic; Aysenil Belger; Daniel H Mathalon; Judith M Ford; Guia Guffanti; Fabio Macciardi; Steven G Potkin; Theo G M van Erp

doi:10.1016/j.schres.2018.05.041

Polygenic risk score, genome-wide association, and gene set analyses of cognitive domain deficits in schizophrenia

Schizophr Res. 2018 Nov:201:393-399. doi: 10.1016/j.schres.2018.05.041. Epub 2018 Jun 12.

Authors

Soichiro Nakahara¹, Sarah Medland², Jessica A Turner³, Vince D Calhoun⁴, Kelvin O Lim⁵, Bryon A Mueller⁶, Juan R Bustillo⁵, Daniel S O'Leary⁷, Jatin G Vaidya⁷, Sarah McEwen⁸, James Voyvodic⁹, Aysenil Belger¹⁰, Daniel H Mathalon¹¹, Judith M Ford¹¹, Guia Guffanti¹², Fabio Macciardi¹³, Steven G Potkin¹³, Theo G M van Erp¹⁴

Affiliations

¹ Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92617, United States; Unit 2, Candidate Discovery Science Labs, Drug Discovery Research, Astellas Pharma Inc, 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
² Psychiatric Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia.
³ Departments of Psychology and Neuroscience, Georgia State University, Atlanta, GA, United States; Mind Research Network, Albuquerque, NM 87106, United States.
⁴ Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM, United States; Departments of Psychiatry & Neuroscience, University of New Mexico, Albuquerque, NM 87131, United States; Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, United States.
⁵ Departments of Psychiatry & Neuroscience, University of New Mexico, Albuquerque, NM 87131, United States.
⁶ Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, United States.
⁷ Department of Psychiatry, University of Iowa, Iowa City, IA 52242, United States.
⁸ Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, United States.
⁹ Brain Imaging and Analysis Center, Duke University Medical Center, Durham, NC 27710, United States.
¹⁰ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.
¹¹ Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94143, United States; Veterans Affairs San Francisco Healthcare System, San Francisco, CA 94121, United States.
¹² Department of Psychiatry at Harvard Medical School and Computational Genomics Lab at McLean Hospital, Boston, United States.
¹³ Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92617, United States.
¹⁴ Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92617, United States. Electronic address: tvanerp@uci.edu.

Abstract

This study assessed genetic contributions to six cognitive domains, identified by the MATRICS Cognitive Consensus Battery as relevant for schizophrenia, cognition-enhancing, clinical trials. Psychiatric Genomics Consortium Schizophrenia polygenic risk scores showed significant negative correlations with each cognitive domain. Genome-wide association analyses identified loci associated with attention/vigilance (rs830786 within HNF4G), verbal memory (rs67017972 near NDUFS4), and reasoning/problem solving (rs76872642 within HDAC9). Gene set analysis identified unique and shared genes across cognitive domains. These findings suggest involvement of common and unique mechanisms across cognitive domains and may contribute to the discovery of new therapeutic targets to treat cognitive deficits in schizophrenia.

Keywords: GWAS; MCCB; Neuropsychology; PRS; Schizophrenia.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adult
Cognitive Dysfunction / genetics*
Female
Genetic Loci
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Male
Multifactorial Inheritance*
Schizophrenia / genetics*
Schizophrenic Psychology*

Abstract

Publication types

MeSH terms

Grants and funding