Journal
PLOS ONE
Volume 8, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0053042
Keywords
-
Categories
Funding
- Suna and Inan Kirac Foundation
- Scientific and Technological Research Council of Turkey [SBAG 109S075]
- Bogazici University Research Funds [BAP 6055]
- National Institute of Mental Health (NIMH) [N01MH900001, MH074027]
- Genomics Research Branch at NIMH
- Genetic Association Information Network (GAIN)
- NIMH Schizophrenia Genetics Initiative [U01s: MH46276, MH46289, MH46318]
- MGS Part 1 (MGS1) [R01s: MH67257, MH59588, MH59571, MH59565, MH59587, MH60870, MH59566, MH59586, MH61675, MH60879]
- MGS Part 2 (MGS2) [R01s: MH67257, MH59588, MH59571, MH59565, MH59587, MH60870, MH59566, MH59586, MH61675, MH60879]
- [MGS U01s: MH79469]
- [MH79470]
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Schizophrenia is one of the most common and complex neuropsychiatric disorders, which is contributed both by genetic and environmental exposures. Recently, it is shown that NRG1-mediated ErbB4 signalling regulates many important cellular and molecular processes such as cellular growth, differentiation and death, particularly in myelin-producing cells, glia and neurons. Recent association studies have revealed genomic regions of NRG1 and ERBB4, which are significantly associated with risk of developing schizophrenia; however, inconsistencies exist in terms of validation of findings between distinct populations. In this study, we aim to validate the previously identified regions and to discover novel haplotypes of NRG1 and ERBB4 using logistic regression models and Haploview analyses in three independent datasets from GWAS conducted on European subjects, namely, CATIE, GAIN and nonGAIN. We identified a significant 6-kb block in ERBB4 between chromosome locations 212,156,823 and 212,162,848 in CATIE and GAIN datasets (p = 0.0206 and 0.0095, respectively). In NRG1, a significant 25-kb block, between 32,291,552 and 32,317,192, was associated with risk of schizophrenia in all CATIE, GAIN, and nonGAIN datasets (p = 0.0005, 0.0589, and 0.0143, respectively). Fine mapping and FastSNP analysis of genetic variation located within significantly associated regions proved the presence of binding sites for several transcription factors such as SRY, SOX5, CEPB, and ETS1. In this study, we have discovered and validated haplotypes of ERBB4 and NRG1 in three independent European populations. These findings suggest that these haplotypes play an important role in the development of schizophrenia by affecting transcription factor binding affinity.
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