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Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes.

ABSTRACT: 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. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.

SUBMITTER: Smith EN

PROVIDER: S-EPMC3128104 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes.

Smith Erin N EN Koller Daniel L DL Panganiban Corrie C Szelinger Szabolcs S Zhang Peng P Badner Judith A JA Barrett Thomas B TB Berrettini Wade H WH Bloss Cinnamon S CS Byerley William W Coryell William W Edenberg Howard J HJ Foroud Tatiana T Gershon Elliot S ES Greenwood Tiffany A TA Guo Yiran Y Hipolito Maria M Keating Brendan J BJ Lawson William B WB Liu Chunyu C Mahon Pamela B PB McInnis Melvin G MG McMahon Francis J FJ McKinney Rebecca R Murray Sarah S SS Nievergelt Caroline M CM Nurnberger John I JI Nwulia Evaristus A EA Potash James B JB Rice John J Schulze Thomas G TG Scheftner William A WA Shilling Paul D PD Zandi Peter P PP Zöllner Sebastian S Craig David W DW Schork Nicholas J NJ Kelsoe John R JR

PLoS genetics 20110630 6

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 geno ...[more]

PMID: 21738484

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Project description:Several genes that are involved in the regulation of circadian rhythms are implicated in the susceptibility to bipolar disorder (BD). The current study aimed to investigate the relationships between genetic variants in NR1D1 RORA, and RORB genes and BD in the Han Chinese population. We conducted a case-control genetic association study with two samples of BD patients and healthy controls. Sample I consisted of 280 BD patients and 200 controls. Sample II consisted of 448 BD patients and 1770 healthy controls. 27 single nucleotide polymorphisms in the NR1D1, RORA, and RORB genes were genotyped using GoldenGate VeraCode assays in sample I, and 492 markers in the three genes were genotyped using Affymetrix Genome-Wide CHB Array in sample II. Single marker and gene-based association analyses were performed using PLINK. A combined p-value for the joining effects of all markers within a gene was calculated using the rank truncated product method. Multifactor dimensionality reduction (MDR) method was also applied to test gene-gene interactions in sample I. All markers were in Hardy-Weinberg equilibrium (P>0.001). In sample I, the associations with BD were observed for rs4774388 in RORA (OR = 1.53, empirical p-value, P = 0.024), and rs1327836 in RORB (OR = 1.75, P = 0.003). In Sample II, there were 45 SNPs showed associations with BD, and the most significant marker in RORA was rs11639084 (OR = 0.69, P = 0.002), and in RORB was rs17611535 (OR = 3.15, P = 0.027). A combined p-value of 1.6×10-6, 0.7, and 1.0 was obtained for RORA, RORB and NR1D1, respectively, indicting a strong association for RORA with the risk of developing BD. A four way interaction was found among markers in NR1D1, RORA, and RORB with the testing accuracy 53.25% and a cross-validation consistency of 8 out of 10. In sample II, 45 markers had empirical p-values less than 0.05. The most significant markers in RORA and RORB genes were rs11639084 (OR = 0.69, P = 0.002), and rs17611535 (OR = 3.15, P = 0.027), respectively. Gene-based association was significant for RORA gene (P = 0.0007). Our results support for the involvement of RORs genes in the risk of developing BD. Investigation of the functional properties of genes in the circadian pathway may further enhance our understanding about the pathogenesis of bipolar illness.

Dataset Information

Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes.

Publications

Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes.

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