Molecular evolution in the CREB1 signal pathway and a rare haplotype in CREB1 with genetic predisposition to schizophrenia

Liang Ma; Dong-Dong Wu; Suk Ling Ma; Liwen Tan; Xiaogang Chen; Nelson L S Tang; Yong-Gang Yao

doi:10.1016/j.jpsychires.2014.06.008

Molecular evolution in the CREB1 signal pathway and a rare haplotype in CREB1 with genetic predisposition to schizophrenia

J Psychiatr Res. 2014 Oct:57:84-9. doi: 10.1016/j.jpsychires.2014.06.008. Epub 2014 Jun 24.

Authors

Liang Ma¹, Dong-Dong Wu², Suk Ling Ma³, Liwen Tan⁴, Xiaogang Chen⁴, Nelson L S Tang⁵, Yong-Gang Yao⁶

Affiliations

¹ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
² State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
³ Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong, China.
⁴ Institute of Mental Health, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
⁵ KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, Yunnan, China; Department of Chemical Pathology and Laboratory of Genetics of Disease Susceptibility, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Functional Genomics and Biostatistical Computing Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. Electronic address: nelsontang@cuhk.edu.hk.
⁶ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650201, China; KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, Yunnan, China. Electronic address: yaoyg@mail.kiz.ac.cn.

PMID: 25043418
DOI: 10.1016/j.jpsychires.2014.06.008

Abstract

CREB1 is a cAMP responsive transcriptional factor which plays a key role in neural development. CREB1 signal pathway (CSP) has been implicated repeatedly in studies of predisposition for schizophrenia. We speculated that CSP has undergone positive selection during evolution of modern human and some genes that have undergone natural selection in the past may predispose to schizophrenia (SCZ) in modern time. Positive selection and association analysis were employed to explore the molecular evolution of CSP and association with schizophrenia. Our results showed a pan-ethnic selection event on NRG1 and CREB1, as confirmed in all 14 ethnic populations studied, which also suggested a selection process occurred before the "Out of Africa" scenario. Analysis of 62 SNPs covering 6 CSP genes in 2019 Han Chinese (976 SCZ patients and 1043 healthy individuals) showed an association of two SNPs (rs4379857, P = 0.009, OR [95% CI]: 1.200 [1.379-1.046]; rs2238751, P = 0.023, OR [95% CI]: 1.253 [1.522-1.032]) with SCZ. However, none of these significances survived after multiple testing corrections. Nonetheless, we observed an association of a rare CREB1 haplotype CCGGC (Bonferroni corrected P = 1.74 × 10(-5)) with SCZ. Our study showed that there was substantial population heterogeneity in genetic predisposition to SCZ, and different genes in the CSP pathway may predispose to SCZ in different populations.

Keywords: Association; CREB1 signal pathway; Positive selection; Schizophrenia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Cyclic AMP Response Element-Binding Protein / genetics*
Evolution, Molecular*
Female
Genetic Predisposition to Disease
Haplotypes
Humans
Male
Middle Aged
Neuregulin-1 / genetics*
Polymorphism, Single Nucleotide
Schizophrenia / genetics*
Signal Transduction / genetics*
Young Adult

Substances

CREB1 protein, human
Cyclic AMP Response Element-Binding Protein
NRG1 protein, human
Neuregulin-1