Bipolar Disorder: New BD Risk Loci Identified in Genome-Wide Association Study

In a recent genome-wide association study (GWAS), researchers identified several genes and loci that are involved in the heritable risk of bipolar disorder (BD), as well as a shared genetic basis for BD that spans Han Chinese and European populations. They found one novel locus near TMEM108 that is associated with BD specifically in those of Han Chinese ancestry, and two novel loci near VRK2 and RHEBL1 associated with BD across other ancestries.

According to the World Health Organization, the lifetime prevalence for bipolar I disorder is 0.6% and for bipolar II disorder, 0.4% in 11 countries throughout the world. Previous studies have shown that in first-degree relatives of BD patients, lifetime prevalence of BD is about 5%-10%. In monozygotic co-twins, it soars to 40%-70%. Based on these numbers, heritability of BD is likely.

But heritability of BD can vary based on ancestry, according to these researchers, led by Hui-Juan Li, BS, of the Chinese Academy of Sciences, Kunming, Yunnan, China.

“Although GWASs have increased our knowledge of BD in Europeans, genetic heterogeneity between continental populations exists and may result in uncertainty when generalizing these discoveries across different populations. Because most of the BD GWASs to date have been performed in European populations, further analyses of the genetic architecture of BD in other populations are needed,” they added.

In this study, published in JAMA Psychiatry, Li and colleagues sought to assess the genetic basis of BD in individuals of Han Chinese descent. They conducted a GWAS and independent replication to identify BD risk loci in 1,882 cases (mean age: 35.43 years; 46% male) and 4,650 controls (mean age: 27.48 years; 53% male). The replication sample include 958 cases (mean age: 37.82 years; 43% male) and 2,050 controls (mean age: 27.50 years; 58% male).

Near the gene that encodes transmembrane protein 108 (TMEM108, rs9863544) they discovered a novel BD risk locus (OR: 0.650; 95% CI: 0.559-0.756; P=2.49 x 10^-8). TMEM108 is involved in the development of the dendritic spine, as well as with glutamatergic transmission in the dentate gyrus.

Li and fellow researchers also found evidence of shared BD genetic risk between Han Chinese and European populations upon trans-ancestry genetic correlation estimation and polygenetic risk score analyses. Upon meta-analysis, they identified two new GWAS risk loci near VRK2 (rs41335055; OR: 0.849; 95% CI: 0.804-0.897; P=4.98 x 10^-9) and near RHEBL1 (rs7969091; OR: 0.932; 95% CI: 0.909-0.956; P=3.12 x 10^-8).

Finally, they found that of the 30 loci associated with BD in those of European descent found by the Psychiatric Genomics Consortium—the largest published study on this topic to date, 18 were replicated in the trans-ancestry meta-analysis, 4 had opposite directions of effect across ancestry, and 8 were absent in those of Han Chinese ancestry.

In an accompanying editorial, Niamh Mullins, PhD, of the Icahn School of Medicine at Mount Sinai, New York, NY, and Hailiang Huang, PhD, of the Broad Institute of MIT and Harvard, Cambridge, MA, echoed the paucity of studies in individuals not of European descent.

“Genetic epidemiology studies have estimated the heritability of BD to be approximately 60% to 85%, and GWASs have provided invaluable insights into disease biology. The largest published study to date, conducted by the Psychiatric Genomics Consortium (PGC), identified 30 BD-associated genomic loci in a sample of approximately 30 000 cases. However, most BD GWASs have been conducted in individuals of European ancestry,” they wrote.

“Genetic epidemiology studies have estimated the heritability of BD to be approximately 60% to 85%, and GWASs have provided invaluable insights into disease biology. While [polygenic risk scores] PRS for BD, and indeed most complex diseases, are not currently of clinical utility, there is an urgent need to increase the ancestral diversity of large discovery GWASs to ensure equitable access to future precision medicine possibilities for all populations. Encouragingly, this study contributes to a growing literature on the genetics of BD in individuals of East Asian ancestries, with previous GWASs published in Japanese samples and other Han Chinese samples,” added Mullins and Hailiang.

“Studying the genetics of BD across ancestries presents a plethora of possibilities to advance our understanding of its biological etiology,” they concluded.

Study limitations include the use of European-based data and reference panels and the reliance on self-reported health status instead of screening by physicians.

1. In a genome-wide association study, novel genome-wide significant risk loci for bipolar disorder were found in Han Chinese and European patients.

2. In those of Han Chinese ancestry, researchers found one novel locus near TMEM108 that is associated with BD, and in those of other ancestries, two novel loci near VRK2 and RHEBL1.

E.C. Meszaros, Contributing Writer, BreakingMED™

Cat ID: 496

Topic ID: 495,496,496,497,130,192,54,925