Copy Number Variations in RNF216 and Postsynaptic Membrane-associated Genes Are Associated with Bipolar Disorder: a Case-control Study in the Japanese Population

Aim: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population.

Methods: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%.

Results: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05).

Conclusion: We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.

References

Kushima I, Imaeda M, Tanaka S, Kato H, Oya-Ito T, Nakatochi M . Contribution of copy number variations to the risk of severe eating disorders. Psychiatry Clin Neurosci. 2022; 76(9):423-428. PMC: 9546291. DOI: 10.1111/pcn.13430. View

Akula N, Wendland J, Choi K, McMahon F . An Integrative Genomic Study Implicates the Postsynaptic Density in the Pathogenesis of Bipolar Disorder. Neuropsychopharmacology. 2015; 41(3):886-95. PMC: 4707835. DOI: 10.1038/npp.2015.218. View

Pebrel-Richard C, Rouzade C, Kemeny S, Eymard-Pierre E, Gay-Bellile M, Gouas L . Refinement of the critical region in a new 7p22.1 microduplication syndrome including craniofacial dysmorphism and speech delay. Am J Med Genet A. 2014; 164A(11):2964-7. DOI: 10.1002/ajmg.a.36715. View

Koopmans F, van Nierop P, Andres-Alonso M, Byrnes A, Cijsouw T, Coba M . SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse. Neuron. 2019; 103(2):217-234.e4. PMC: 6764089. DOI: 10.1016/j.neuron.2019.05.002. View

Rigau M, Juan D, Valencia A, Rico D . Intronic CNVs and gene expression variation in human populations. PLoS Genet. 2019; 15(1):e1007902. PMC: 6345438. DOI: 10.1371/journal.pgen.1007902. View

Godoy L, Prizon T, Rossignoli M, Leite J, Liberato J . Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention. Front Integr Neurosci. 2022; 16:765324. PMC: 8891758. DOI: 10.3389/fnint.2022.765324. View

Wu L, Huang M, Fann C, Lane H, Kuo C, Chiu W . Genome-wide association study of early-onset bipolar I disorder in the Han Taiwanese population. Transl Psychiatry. 2021; 11(1):301. PMC: 8137921. DOI: 10.1038/s41398-021-01407-6. View

Merikangas K, Jin R, He J, Kessler R, Lee S, Sampson N . Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011; 68(3):241-51. PMC: 3486639. DOI: 10.1001/archgenpsychiatry.2011.12. View

Nakatochi M, Kushima I, Ozaki N . Implications of germline copy-number variations in psychiatric disorders: review of large-scale genetic studies. J Hum Genet. 2020; 66(1):25-37. DOI: 10.1038/s10038-020-00838-1. View

10.

Charney A, Stahl E, Green E, Chen C, Moran J, Chambert K . Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases. Biol Psychiatry. 2019; 86(2):110-119. PMC: 6586545. DOI: 10.1016/j.biopsych.2018.12.009. View

11.

McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A . The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry. 2003; 60(5):497-502. DOI: 10.1001/archpsyc.60.5.497. View

12.

Edvardsen J, Torgersen S, Roysamb E, Lygren S, Skre I, Onstad S . Heritability of bipolar spectrum disorders. Unity or heterogeneity?. J Affect Disord. 2007; 106(3):229-40. DOI: 10.1016/j.jad.2007.07.001. View

13.

Malhotra D, McCarthy S, Michaelson J, Vacic V, Burdick K, Yoon S . High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron. 2011; 72(6):951-63. PMC: 3921625. DOI: 10.1016/j.neuron.2011.11.007. View

14.

Fatemi S, Folsom T, Rooney R, Thuras P . mRNA and protein expression for novel GABAA receptors θ and ρ2 are altered in schizophrenia and mood disorders; relevance to FMRP-mGluR5 signaling pathway. Transl Psychiatry. 2013; 3:e271. PMC: 3693405. DOI: 10.1038/tp.2013.46. View

15.

Preiksaitiene E, Kasnauskiene J, Ciuladaite Z, Tumiene B, Patsalis P, Kucinskas V . Clinical and molecular characterization of a second case of 7p22.1 microduplication. Am J Med Genet A. 2012; 158A(5):1200-3. DOI: 10.1002/ajmg.a.35300. View

16.

Sekiguchi M, Sobue A, Kushima I, Wang C, Arioka Y, Kato H . ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk. Transl Psychiatry. 2020; 10(1):247. PMC: 7376022. DOI: 10.1038/s41398-020-00917-z. View

17.

Chen J, Calhoun V, Perrone-Bizzozero N, Pearlson G, Sui J, Du Y . A pilot study on commonality and specificity of copy number variants in schizophrenia and bipolar disorder. Transl Psychiatry. 2016; 6(5):e824. PMC: 5545651. DOI: 10.1038/tp.2016.96. View

18.

Kushima I, Aleksic B, Kimura H, Nakatochi M, Lo T, Ikeda M . X chromosome aneuploidies and schizophrenia: association analysis and phenotypic characterization. Psychiatry Clin Neurosci. 2022; 76(12):667-673. PMC: 10086948. DOI: 10.1111/pcn.13474. View

19.

Kataoka M, Matoba N, Sawada T, Kazuno A, Ishiwata M, Fujii K . Exome sequencing for bipolar disorder points to roles of de novo loss-of-function and protein-altering mutations. Mol Psychiatry. 2016; 21(7):885-93. PMC: 5414074. DOI: 10.1038/mp.2016.69. View

20.

Goes F, Pirooznia M, Tehan M, Zandi P, McGrath J, Wolyniec P . De novo variation in bipolar disorder. Mol Psychiatry. 2019; 26(8):4127-4136. PMC: 10754065. DOI: 10.1038/s41380-019-0611-1. View