A molecule-based genetic association approach implicates a range of voltage-gated calcium channels associated with schizophrenia

Li, Wen and Fan, Chun Chieh and Mäki-Marttunen, Tuomo and Thompson, Wesley K and Schork, Andrew J and Bettella, Francesco and Djurovic, Srdjan and Dale, Anders M and Andreassen, Ole A and Wang, Yunpeng and Knight, Jo (2018) A molecule-based genetic association approach implicates a range of voltage-gated calcium channels associated with schizophrenia. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 177 (4). pp. 454-467. ISSN 1552-4841

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Abstract

Traditional genome-wide association studies (GWAS) have successfully detected genetic variants associated with schizophrenia. However, only a small fraction of heritability can be explained. Gene-set/pathway-based methods can overcome limitations arising from single nucleotide polymorphism (SNP)-based analysis, but most of them place constraints on size which may exclude highly specific and functional sets, like macromolecules. Voltage-gated calcium (Cav ) channels, belonging to macromolecules, are composed of several subunits whose encoding genes are located far away or even on different chromosomes. We combined information about such molecules with GWAS data to investigate how functional channels associated with schizophrenia. We defined a biologically meaningful SNP-set based on channel structure and performed an association study by using a validated method: SNP-set (sequence) kernel association test. We identified eight subtypes of Cav channels significantly associated with schizophrenia from a subsample of published data (N = 56,605), including the L-type channels (Cav 1.1, Cav 1.2, Cav 1.3), P-/Q-type Cav 2.1, N-type Cav 2.2, R-type Cav 2.3, T-type Cav 3.1, and Cav 3.3. Only genes from Cav 1.2 and Cav 3.3 have been implicated by the largest GWAS (N = 82,315). Each subtype of Cav channels showed relatively high chip heritability, proportional to the size of its constituent gene regions. The results suggest that abnormalities of Cav channels may play an important role in the pathophysiology of schizophrenia and these channels may represent appropriate drug targets for therapeutics. Analyzing subunit-encoding genes of a macromolecule in aggregate is a complementary way to identify more genetic variants of polygenic diseases. This study offers the potential of power for discovery the biological mechanisms of schizophrenia.

Item Type:
Journal Article
Journal or Publication Title:
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Additional Information:
This is the peer reviewed version of the following article: Li W, Fan CC, Mäki‐Marttunen T, et al. A molecule‐based genetic association approach implicates a range of voltage‐gated calcium channels associated with schizophrenia. Am J Med Genet Part B. 2018;177B:454–467. https://doi.org/10.1002/ajmg.b.32634 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/ajmg.b.32634/abstract This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2700/2738
Subjects:
ID Code:
126539
Deposited By:
Deposited On:
11 Sep 2018 11:02
Refereed?:
Yes
Published?:
Published
Last Modified:
14 Aug 2020 05:00