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Schizophr Bull. 2019 Jan 1;45(1):222-232. doi: 10.1093/schbul/sby010.

Shared Genetic Risk of Schizophrenia and Gray Matter Reduction in 6p22.1.

Author information

1
The Mind Research Network, Albuquerque, NM.
2
Department of Electrical Engineering, University of New Mexico, Albuquerque, NM.
3
Department of Neurosciences and Psychiatry, University of New Mexico School of Medicine, Albuquerque, NM.
4
Department of Psychiatry, University of New Mexico School of Medicine, Albuquerque, NM.
5
Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT.
6
Department of Psychiatry, Yale University, New Haven, CT.
7
Department of Neuroscience, Yale University, New Haven, CT.
8
Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, CA.
9
MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA.
10
Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Germany.
11
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA.
12
Department of Psychiatry, University of Minnesota, Minneapolis, MN.
13
Minneapolis Veterans Administration Health Care System, Minneapolis, MN.
14
Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL.
15
Department of Radiology, Northwestern University, Chicago, IL.
16
Department of Psychology, University of New Mexico, Albuquerque, NM.
17
Department of Psychology, University of Georgia, Athens, GA.
18
Department of Psychiatry, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA.
19
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL.
20
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH.
21
Department of Psychiatry, UT Southwestern Medical School, Dallas, TX.
22
Norwegian Centre for Mental Disorders Research (NORMENT), KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Norway.
23
Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
24
Department of Psychology, University of Oslo, Oslo, Norway.
25
National Laboratory of Pattern Recognition, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
26
Psychology Department and Neuroscience Institute, Georgia State University, Atlanta, GA.

Abstract

Genetic factors are known to influence both risk for schizophrenia (SZ) and variation in brain structure. A pressing question is whether the genetic underpinnings of brain phenotype and the disorder overlap. Using multivariate analytic methods and focusing on 1,402 common single-nucleotide polymorphisms (SNPs) mapped from the Psychiatric Genomics Consortium (PGC) 108 regions, in 777 discovery samples, we identified 39 SNPs to be significantly associated with SZ-discriminating gray matter volume (GMV) reduction in inferior parietal and superior temporal regions. The findings were replicated in 609 independent samples. These 39 SNPs in chr6:28308034-28684183 (6p22.1), the most significant SZ-risk region reported by PGC, showed regulatory effects on both DNA methylation and gene expression of postmortem brain tissue and saliva. Furthermore, the regulated methylation site and gene showed significantly different levels of methylation and expression in the prefrontal cortex between cases and controls. In addition, for one regulated methylation site we observed a significant in vivo methylation-GMV association in saliva, suggesting a potential SNP-methylation-GMV pathway. Notably, the risk alleles inferred for GMV reduction from in vivo imaging are all consistent with the risk alleles for SZ inferred from postmortem data. Collectively, we provide evidence for shared genetic risk of SZ and regional GMV reduction in 6p22.1 and demonstrate potential molecular mechanisms that may drive the observed in vivo associations. This study motivates dissecting SZ-risk variants to better understand their associations with focal brain phenotypes and the complex pathophysiology of the illness.

PMID:
29474680
DOI:
10.1093/schbul/sby010

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