Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder (original) (raw)
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Genome-wide association study reveals two new risk loci for bipolar disorder
Nature communications, 2014
Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.
2016
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324,p= 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959,p= 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked m...
2020
Background. Although accurate differentiation between bipolar disorder (BD) and unipolar major depressive disorder (MDD) has important prognostic and therapeutic implications, the distinction is often challenging based on clinical grounds alone. In this study, we tested whether psychiatric polygenic risk scores (PRSs) improve clinically based classification models of BD v. MDD diagnosis. Methods. Our sample included 843 BD and 930 MDD subjects similarly genotyped and phenotyped using the same standardized interview. We performed multivariate modeling and receiver operating characteristic analysis, testing the incremental effect of PRSs on a baseline model with clinical symptoms and features known to associate with BD compared with MDD status. Results. We found a strong association between a BD diagnosis and PRSs drawn from BD (R = 3.5%, p = 4.94 × 10) and schizophrenia (R = 3.2%, p = 5.71 × 10) genome-wide association meta-analyses. Individuals with top decile BD PRS had a significa...
PLoS genetics, 2011
Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10(-7)). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. Th...