Novel Risk Loci Associated With Genetic Risk for Bipolar Disorder Among Han Chinese Individuals

Abstract

IMPORTANCEThe genetic basis of bipolar disorder (BD) in Han Chinese individuals is not fully understood.OBJECTIVE To explore the genetic basis of BD in the Han Chinese population. DESIGN, SETTING, AND PARTICIPANTSA genome-wide association study (GWAS), followed by independent replication, was conducted to identify BD risk loci in Han Chinese individuals. Individuals with BD were diagnosed based on DSM-IV criteria and had no history of schizophrenia, mental retardation, or substance dependence; individuals without any personal or family history of mental illnesses, including BD, were included as control participants. In total, discovery samples from 1822 patients and 4650 control participants passed quality control for the GWAS analysis. Replication analyses of samples from 958 patients and 2050 control participants were conducted. Summary statistics from the European Psychiatric Genomics Consortium 2 (PGC2) BD GWAS (20 352 cases and 31 358 controls) were used for the trans-ancestry genetic correlation analysis, polygenetic risk score analysis, and meta-analysis to compare BD genetic risk between Han Chinese and European individuals. The study was performed in February 2020.MAIN OUTCOMES AND MEASURES Single-nucleotide variations with P < 5.00 × 10 −8 were considered to show genome-wide significance of statistical association. RESULTS The HanChinese discovery GWAS sample included 1822 cases (mean [SD] age, 35.43 [14.12] years; 838 [46%] male) and 4650 controls (mean [SD] age, 27.48 [5.97] years; 2465 [53%] male), and the replication sample included 958 cases (mean [SD] age, 37.82 [15.54] years; 412 [43%] male) and 2050 controls (mean [SD] age, 27.50 [6.00] years; 1189[58%] male). A novel BD risk locus in Han Chinese individuals was found near the gene encoding transmembrane protein 108 (TMEM108, rs9863544; P = 2.49 × 10 −8 ; odds ratio [OR], 0.650; 95% CI, 0.559-0.756), which is required for dendritic spine development and glutamatergic transmission in the dentate gyrus. Trans-ancestry genetic correlation estimation (ρ ge = 0.652, SE = 0.106; P = 7.30 × 10 −10 ) and polygenetic risk score analyses (maximum liability-scaled Nagelkerke pseudo R 2 = 1.27%; P = 1.30 × 10 −19 ) showed evidence of shared BD genetic risk between Han Chinese and European populations, and meta-analysis identified 2 new GWAS risk loci near VRK2 (rs41335055; P = 4.98 × 10 −9 ; OR, 0.849; 95% CI, 0.804-0.897) and RHEBL1 (rs7969091; P = 3.12 × 10 −8 ; OR, 0.932; 95% CI, 0.909-0.956).CONCLUSIONS AND RELEVANCE This GWAS study identified several loci and genes involved in the heritable risk of BD, providing insights into its genetic architecture and biological basis.

Identification of Gene Loci That Overlap Between Mental Disorders and Poor Prognosis of Cancers

“…Twelve relatively recent and comprehensive articles were identified based on screening criteria ( 21 – 32 ) and psychiatric disorder-related genes were obtained from selected published articles ( Table 1 ). A total of 239 genes were collected, including 44 bipolar disorder-related genes, 13 anxiety-related genes, 8 schizophrenia-related genes, 11 OCD-related genes, 14 autism-related genes, 10 PTSD-related genes, 90 depression-related genes, and 58 suicide-related genes.…”

Transmembrane Protein 108 Inhibits the Proliferation and Myelination of Oligodendrocyte Lineage Cells in the Corpus Callosum

“…Strikingly, one recent GWAS screened BD risk loci in the Han Chinese population, covering 1822 BD patients and 4650 control individuals, and the data was replicated analysis. After nally multiple analyses between Han Chinese and European populations, a new SNP (rs9863544) in BD patients were found, locating in the upstream regulatory region of the Tmem108 gene [13]. Tmem108 expression change may be one of the onset reasons of the related psychiatry diseases.…”

“…Potential multiple functions of Tmem108 in the CNS Tmem108, also known as Retrolinkin [19,34,35], is located on human chromosome 3q21. GWAS found that TMEM108 is not only related to substance addiction [36], smoking withdrawal [37], and alcohol addiction [38][39][40][41], but also is a susceptibility gene of SCZ [11,12,14] and BD [11][12][13].…”

The Candidate Schizophrenia Risk Gene Tmem108 Regulates Glucose Metabolism Homeostasis

“…TMEM108 is a single transmembrane glycoprotein. It is linked with several psychiatric disorders in genome-wide association studies (GWAS), such as bipolar disorder (10)(11)(12), alcoholism (13), major depression (14), and SCZ (10,11,(15)(16)(17). A single nucleotide polymorphism (SNP) (rs7624858) site, located in the intron of Tmem108, is linked to SCZ in GWAS (15).…”

“…Tmem108 is expressed as early as E8.5 in the central nervous system (CNS) (18,19) and is a multi-function molecular in a recent study (12,(20)(21)(22). TMEM108, also known as Retrolinkin (23)(24)(25), promotes endosomal vesicle retrograde transport in sensory neuronal axons by directly interacting with the dynastic/ dynein cargo adaptor BPAG1n4 (25).…”