Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies

Chung-Feng Kao; Hui-Wen Chen; Hsi-Chung Chen; Jenn-Hwai Yang; Ming-Chyi Huang; Yi-Hang Chiu; Shih-Ku Lin; Ya-Chin Lee; Chih-Min Liu; Li-Chung Chuang; Chien-Hsiun Chen; Jer-Yuarn Wu; Ru-Band Lu; Po-Hsiu Kuo

doi:10.1093/ijnp/pyw064

Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies

Int J Neuropsychopharmacol. 2016 Dec 3;19(12):pyw064. doi: 10.1093/ijnp/pyw064. Print 2016 Dec.

Authors

Affiliations

¹ Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan (Dr Kao, Mr Lee, and Dr Kuo); Department of Agronomy, College of Agriculture & Natural Resources, National Chung Hsing University, Taichung, Taiwan (Dr Kao); National Center for Genome Medicine, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (Mrs Chen, Dr Yang, Dr Chen, and Dr Wu); Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan (Dr Chen); Department of Nursing, Cardinal Tien Junior College of Healthcare & Management, Yilan, Taiwan (Dr Chuang); Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan (Drs Huang, Chiu, and Lin); Department of Psychiatry, Taipei City Psychiatric Center, Taipei, Taiwan (Dr Huang); Department of Psychiatry, Wan Fang Medical Center, Taipei, Taiwan (Dr Chiu); Department of Psychiatry, Taipei City Hospital and Psychiatric Center, Taipei, Taiwan (Dr Lin); Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan (Dr Liu); Department of Psychiatry, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan (Dr Liu); Department of Psychiatry, National Cheng Kung University and Hospital, Tainan, Taiwan (Dr Lu); Research Center for Genes, Environment and Human Health, National Taiwan University, Taipei, Taiwan (Dr Kuo).
² Department of Public Health & Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan (Dr Kao, Mr Lee, and Dr Kuo); Department of Agronomy, College of Agriculture & Natural Resources, National Chung Hsing University, Taichung, Taiwan (Dr Kao); National Center for Genome Medicine, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (Mrs Chen, Dr Yang, Dr Chen, and Dr Wu); Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan (Dr Chen); Department of Nursing, Cardinal Tien Junior College of Healthcare & Management, Yilan, Taiwan (Dr Chuang); Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan (Drs Huang, Chiu, and Lin); Department of Psychiatry, Taipei City Psychiatric Center, Taipei, Taiwan (Dr Huang); Department of Psychiatry, Wan Fang Medical Center, Taipei, Taiwan (Dr Chiu); Department of Psychiatry, Taipei City Hospital and Psychiatric Center, Taipei, Taiwan (Dr Lin); Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan (Dr Liu); Department of Psychiatry, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan (Dr Liu); Department of Psychiatry, National Cheng Kung University and Hospital, Tainan, Taiwan (Dr Lu); Research Center for Genes, Environment and Human Health, National Taiwan University, Taipei, Taiwan (Dr Kuo). phkuo@ntu.edu.tw rblu@mail.ncku.edu.tw.

Abstract

Background: This study aimed to identify susceptible loci and enriched pathways for bipolar disorder subtype II.

Methods: We conducted a genome-wide association scan in discovery samples with 189 bipolar disorder subtype II patients and 1773 controls, and replication samples with 283 bipolar disorder subtype II patients and 500 controls in a Taiwanese Han population using Affymetrix Axiom Genome-Wide CHB1 Array. We performed single-marker and gene-based association analyses, as well as calculated polygeneic risk scores for bipolar disorder subtype II. Pathway enrichment analyses were employed to reveal significant biological pathways.

Results: Seven markers were found to be associated with bipolar disorder subtype II in meta-analysis combining both discovery and replication samples (P<5.0×10^-6), including markers in or close to MYO16, HSP90AB3P, noncoding gene LOC100507632, and markers in chromosomes 4 and 10. A novel locus, ETF1, was associated with bipolar disorder subtype II (P<6.0×10^-3) in gene-based association tests. Results of risk evaluation demonstrated that higher genetic risk scores were able to distinguish bipolar disorder subtype II patients from healthy controls in both discovery (P=3.9×10^-4~1.0×10^-3) and replication samples (2.8×10^-4~1.7×10^-3). Genetic variance explained by chip markers for bipolar disorder subtype II was substantial in the discovery (55.1%) and replication (60.5%) samples. Moreover, pathways related to neurodevelopmental function, signal transduction, neuronal system, and cell adhesion molecules were significantly associated with bipolar disorder subtype II.

Conclusion: We reported novel susceptible loci for pure bipolar subtype II disorder that is less addressed in the literature. Future studies are needed to confirm the roles of these loci for bipolar disorder subtype II.

Keywords: bipolar II disorder; enriched pathways; genome-wide association; heritability estimate; polygenic score.

Publication types

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

MeSH terms

Adolescent
Adult
Aged
Bipolar Disorder / diagnosis
Bipolar Disorder / genetics*
Bipolar Disorder / psychology
Case-Control Studies
Female
Gene Expression Profiling / methods
Gene Frequency
Gene Regulatory Networks*
Genetic Loci*
Genetic Markers
Genetic Predisposition to Disease
Genome-Wide Association Study
Heredity
Humans
Male
Middle Aged
Multifactorial Inheritance
Oligonucleotide Array Sequence Analysis
Phenotype
Polymorphism, Single Nucleotide*
Risk Assessment
Risk Factors
Taiwan
Young Adult

Substances

Genetic Markers