Genetic Basis Of Bipolar Disorder Research Articles

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

The genetic basis of bipolar disorder (BD) in Han Chinese individuals is not fully understood. To explore the genetic basis of BD in the Han Chinese population. A 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. Single-nucleotide variations with P < 5.00 × 10-8 were considered to show genome-wide significance of statistical association. The Han Chinese 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 (ρge = 0.652, SE = 0.106; P = 7.30 × 10-10) and polygenetic risk score analyses (maximum liability-scaled Nagelkerke pseudo R2 = 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). This GWAS study identified several loci and genes involved in the heritable risk of BD, providing insights into its genetic architecture and biological basis.

Clinical and genetic validity of quantitative bipolarity

Research has yet to provide a comprehensive understanding of the genetic basis of bipolar disorder (BP). In genetic studies, defining the phenotype by diagnosis may miss risk-allele carriers without BP. The authors aimed to test whether quantitatively detected subclinical symptoms of bipolarity identifies a heritable trait that infers risk for BP. The Quantitative Bipolarity Scale (QBS) was administered to 310 Old Order Amish or Mennonite individuals from multigenerational pedigrees; 110 individuals had psychiatric diagnoses (20 BP, 61 major depressive disorders (MDD), 3 psychotic disorders, 26 other psychiatric disorders). Familial aggregation of QBS was calculated using the variance components method to derive heritability and shared household effects. The QBS score was significantly higher in BP subjects (31.5 ± 3.6) compared to MDD (16.7 ± 2.0), other psychiatric diagnoses (7.0 ± 1.9), and no psychiatric diagnosis (6.0 ± 0.65) (all p < 0.001). QBS in the whole sample was significantly heritable (h2 = 0.46 ± 0.15, p < 0.001) while the variance attributed to the shared household effect was not significant (p = 0.073). When subjects with psychiatric illness were removed, the QBS heritability was similar (h2 = 0.59 ± 0.18, p < 0.001). These findings suggest that quantitative bipolarity as measured by QBS can separate BP from other psychiatric illnesses yet is significantly heritable with and without BP included in the pedigrees suggesting that the quantitative bipolarity describes a continuous heritable trait that is not driven by a discrete psychiatric diagnosis. Bipolarity trait assessment may be used to supplement the diagnosis of BP in future genetic studies and could be especially useful for capturing subclinical genetic contributions to a BP phenotype.

F126. Quantitative Bipolarity and its Heritability

The search for a genetic basis of bipolar disorder (BP) has been inconclusive. In genetic studies, defining the phenotype by diagnosis may miss risk-allele carriers without BP, wrongly grouping them into control groups. We hypothesize that a quantitative bipolarity assessment may identify a trait that tags BP patients but also those with increased risk for BP, and is still heritable.

Promising 2-Pronged Approach to Genetic Basis of Bipolar Disorder.

Promising 2-Pronged Approach to Genetic Basis of Bipolar Disorder.

Candidate region linkage analysis in twins discordant or concordant for depression symptomatology

Genetic risk factors contribute considerably to both clinical affective disorders and subsyndromal mood level. There is moreover evidence to suggest that the genetic basis of bipolar disorder and unipolar depression overlap to some extent, and several linkage analyses have suggested evidence for a common susceptibility locus in affective disorders on chromosome 12q24. In this study we investigated the chromosome 12 candidate region for linkage to the mean level of depression symptomatology, over a 10-year follow-up, using a highly informative sample of concordant and discordant twin pairs selected from 4,731 participants of the Longitudinal Study of Ageing Danish Twins. Our results showed suggestive evidence of linkage to this region with a peak LOD score of 1.91 for marker D12S1634 located at 148 cM, and thus indicates that the previously identified disease locus at 12q24 is also a general vulnerability locus affecting the normal range of mood.

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder.

The genetic basis of bipolar disorder has long been thought to be complex, with the potential involvement of multiple genes, but methods to analyze populations with respect to this complexity have only recently become available. We have carried out a genome-wide association study of bipolar disorder by genotyping over 550,000 single-nucleotide polymorphisms (SNPs) in two independent case-control samples of European origin. The initial association screen was performed using pooled DNA, and selected SNPs were confirmed by individual genotyping. While DNA pooling reduces power to detect genetic associations, there is a substantial cost saving and gain in efficiency. A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest: no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P=1.5 x 10(-8), experiment-wide P<0.01, OR=1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease.

Evidence of linkage and association on 18p11.2 for psychosis

The genetic basis of bipolar disorder (BPD) and schizophrenia (SCZ) has been established through numerous clinical and molecular studies. Although often considered separate nosological entities, evidence now suggests that the two syndromes may share some genetic liability. Recent studies have used a composite phenotype (psychosis) that includes BPD, SCZ, psychosis not otherwise specified, and schizoaffective disorder, to identify shared susceptibility loci. Several chromosomal regions are reported to be shared between these syndromes (18p, 6q, 10p, 13q, 22q). As a part of our endeavor to scan these regions, we report a positive linkage and association finding at 18p11.2 for psychosis. Two-point linkage analysis performed on a series of 52 multiplex pedigrees with 23 polymorphic markers yielded a LOD score of 2.02 at D18S37. An independent set of 159 parent offspring trios was used to confirm this suggestive finding. The TDT analysis yielded support for association between the marker D18S453 and the disease allele (chi2 = 4.829, P < 0.028). This region has been implicated by several studies on BPD [Sjoholt et al. (2004); Mol Psychiatry 9(6):621-629; Washizuka et al. (2004); Biol Psychiatry 56(7):483-489; Pickard et al. (2005); Psychiatr Genet 15(1):37-44], SCZ [Kikuchi et al. (2003); J Med Dent Sci 50(3):225-229; Babovic-Vuksanovic et al. (2004); Am J Med Genet 124(3):318-322] and also as a shared region between the two diseases [Ishiguro et al. (2001); J Neural Transm 108(7):849-854; Reyes et al. (2002); Mol Psychiatry 7(4):337-339; Craddock et al. (2005); J Med Genet 42(3):193-204]. Our findings provide an independent validation of the above reports, and suggest the presence of susceptibility loci for psychoses in this region.

Implications of genetic risk information in families with a high density of bipolar disorder: an exploratory study

While major susceptibility genes for bipolar disorder are yet to be identified, the opportunity exists to systematically ascertain the important issues and societal implications of genetic risk determination for bipolar disorder prior to these technological advances becoming widely available. This study explores, in a sample of families with a high density of bipolar disorder: (i) attitudes to predictive genetic and prenatal testing, using different risk frames; (ii) attributions for bipolar disorder, in particular the degree to which a genetic model is endorsed; and (iii) the impact of these attributions on the perceived stigma of bipolar disorder. A qualitative methodology was selected as most appropriate as no previous research has examined this issue. Participants were ascertained through a molecular genetics study of bipolar disorder. In-depth interviews were conducted with 21 members of families with a high density of bipolar disorder. Most participants reported being interested in genetic testing if it gave a definitive answer, while expressed interest in testing was lower if it gave a probable answer only. Almost all stressed that a genetic susceptibility and environmental factors interacted. Most participants felt that a genetic explanation was likely to decrease the stigma associated with bipolar disorder as it shifted the locus of control and responsibility away from the individual towards the role of heredity. Findings indicate that expressed interest in genetic testing depends on the certainty imparted by the test. Results suggest that families with bipolar disorder are likely to benefit psychologically from information about the genetic basis of bipolar disorder.