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

Jiayu Chen, Vince D. Calhoun, Dongdong Lin, Nora I. Perrone-Bizzozero, Juan R. Bustillo, Godfrey D. Pearlson, Steven G. Potkin, Theo G.M. van Erp, Fabio Macciardi, Stefan Ehrlich, Beng Choon Ho, Scott R. Sponheim, Lei Wang, Julia M. Stephen, Andrew R. Mayer, Faith M. Hanlon, Rex E. Jung, Brett A. Clementz, Matcheri S. Keshavan, Elliot S. GershonJohn A Sweeney, Carol A Tamminga, Ole A. Andreassen, Ingrid Agartz, Lars T. Westlye, Jing Sui, Yuhui Du, Jessica A. Turner, Jingyu Liu

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)222-232
Number of pages11
JournalSchizophrenia Bulletin
Volume45
Issue number1
DOIs
StatePublished - Jan 1 2019

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Schizophrenia
Methylation
Single Nucleotide Polymorphism
Genomics
Saliva
Psychiatry
Brain
Alleles
Phenotype
Brain Diseases
DNA Methylation
Temporal Lobe
Prefrontal Cortex
Gray Matter
Gene Expression
Genes

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Chen, J., Calhoun, V. D., Lin, D., Perrone-Bizzozero, N. I., Bustillo, J. R., Pearlson, G. D., ... Liu, J. (2019). Shared Genetic Risk of Schizophrenia and Gray Matter Reduction in 6p22.1. Schizophrenia Bulletin, 45(1), 222-232. https://doi.org/10.1093/schbul/sby010

Shared Genetic Risk of Schizophrenia and Gray Matter Reduction in 6p22.1. / Chen, Jiayu; Calhoun, Vince D.; Lin, Dongdong; Perrone-Bizzozero, Nora I.; Bustillo, Juan R.; Pearlson, Godfrey D.; Potkin, Steven G.; van Erp, Theo G.M.; Macciardi, Fabio; Ehrlich, Stefan; Ho, Beng Choon; Sponheim, Scott R.; Wang, Lei; Stephen, Julia M.; Mayer, Andrew R.; Hanlon, Faith M.; Jung, Rex E.; Clementz, Brett A.; Keshavan, Matcheri S.; Gershon, Elliot S.; Sweeney, John A; Tamminga, Carol A; Andreassen, Ole A.; Agartz, Ingrid; Westlye, Lars T.; Sui, Jing; Du, Yuhui; Turner, Jessica A.; Liu, Jingyu.

In: Schizophrenia Bulletin, Vol. 45, No. 1, 01.01.2019, p. 222-232.

Research output: Contribution to journalArticle

Chen, J, Calhoun, VD, Lin, D, Perrone-Bizzozero, NI, Bustillo, JR, Pearlson, GD, Potkin, SG, van Erp, TGM, Macciardi, F, Ehrlich, S, Ho, BC, Sponheim, SR, Wang, L, Stephen, JM, Mayer, AR, Hanlon, FM, Jung, RE, Clementz, BA, Keshavan, MS, Gershon, ES, Sweeney, JA, Tamminga, CA, Andreassen, OA, Agartz, I, Westlye, LT, Sui, J, Du, Y, Turner, JA & Liu, J 2019, 'Shared Genetic Risk of Schizophrenia and Gray Matter Reduction in 6p22.1', Schizophrenia Bulletin, vol. 45, no. 1, pp. 222-232. https://doi.org/10.1093/schbul/sby010
Chen J, Calhoun VD, Lin D, Perrone-Bizzozero NI, Bustillo JR, Pearlson GD et al. Shared Genetic Risk of Schizophrenia and Gray Matter Reduction in 6p22.1. Schizophrenia Bulletin. 2019 Jan 1;45(1):222-232. https://doi.org/10.1093/schbul/sby010
Chen, Jiayu ; Calhoun, Vince D. ; Lin, Dongdong ; Perrone-Bizzozero, Nora I. ; Bustillo, Juan R. ; Pearlson, Godfrey D. ; Potkin, Steven G. ; van Erp, Theo G.M. ; Macciardi, Fabio ; Ehrlich, Stefan ; Ho, Beng Choon ; Sponheim, Scott R. ; Wang, Lei ; Stephen, Julia M. ; Mayer, Andrew R. ; Hanlon, Faith M. ; Jung, Rex E. ; Clementz, Brett A. ; Keshavan, Matcheri S. ; Gershon, Elliot S. ; Sweeney, John A ; Tamminga, Carol A ; Andreassen, Ole A. ; Agartz, Ingrid ; Westlye, Lars T. ; Sui, Jing ; Du, Yuhui ; Turner, Jessica A. ; Liu, Jingyu. / Shared Genetic Risk of Schizophrenia and Gray Matter Reduction in 6p22.1. In: Schizophrenia Bulletin. 2019 ; Vol. 45, No. 1. pp. 222-232.
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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.",
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AU - Bustillo, Juan R.

AU - Pearlson, Godfrey D.

AU - Potkin, Steven G.

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AU - Gershon, Elliot S.

AU - Sweeney, John A

AU - Tamminga, Carol A

AU - Andreassen, Ole A.

AU - Agartz, Ingrid

AU - Westlye, Lars T.

AU - Sui, Jing

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