C M Nievergelt

Publications of C M Nievergelt

• Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants.

  Authors: E R Gamazon, J A Badner, L Cheng, C Zhang, D Zhang, N J Cox, E S Gershon, J R Kelsoe, T A Greenwood, C M Nievergelt [......] J B Potash, P P Zandi, P B Mahon, M G McInnis, S Zöllner, P Zhang, D W Craig, S Szelinger, T B Barrett, C Liu

  Molecular psychiatry. 01/2012;

  We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variationWe conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.Molecular Psychiatry advance online publication, 3 January 2012; doi:10.1038/mp.2011.174.

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

  Authors: E. N. Smith, D. L. Koller, C. Panganiban, S. Szelinger, P. Zhang, J. A. Badner, T. B. Barrett, W. H. Berrettini, C. S. Bloss, W. Byerley [......] J. B. Potash, J. Rice, T. G. Schulze, W. A. Scheftner, P. D. Shilling, P. P. Zandi, S. Zollner, D. W. Craig, N. J. Schork, J. R. Kelsoe

  PLoS genetics. 7(6):e1002134.

  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 andAlthough 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 = 1.5x10(-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.

• Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4

  Authors: P. Sklar, S. Ripke, L. J. Scott, O. A. Andreassen, S. Cichon, N. Craddock, H. J. Edenberg, J. I. Nurnberger, M. Rietschel, D. Blackwood [......] G. W. Montgomery, M. Lathrop, H. Oskarsson, M. Bauer, A. Wright, P. B. Mitchell, M. Hautzinger, A. Reif, J. R. Kelsoe, S. M. Purcell

  Nature genetics. 43(10):977-83.

  We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication studyWe conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 x 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.

• Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.

  Authors: P. Sklar, S. Ripke, L. J. Scott, O. A. Andreassen, S. Cichon, N. Craddock, H. J. Edenberg, J. I. Nurnberger, M. Rietschel, D. Blackwood [......] E. Scolnick, S. Djurovic, I. Melle, G. Morken, M. Gill, D. Morris, E. Quinn, T. W. Mühleisen, F. A. Degenhardt, M. Mattheisen et al

  43:977-83.

  We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication studyWe conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.

• Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.

  Authors: P Sklar, S Ripke, L J Scott, O A Andreassen, S Cichon, N Craddock, H J Edenberg, J I Nurnberger, M Rietschel, D Blackwood [......] S Djurovic, I Melle, G Morken, M Gill, D Morris, E Quinn, T W Mühleisen, F A Degenhardt, M Mattheisen, others

  Nat Genet. 43(10):977-83.

  We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication studyWe conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.

• Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.

  Authors: P. Sklar, S. Ripke, L. J. Scott, O. A. Andreassen, S. Cichon, N. Craddock, H. J. Edenberg, J. I. Nurnberger, M. Rietschel, D. Blackwood [......] E. Scolnick, S. Djurovic, I. Melle, G. Morken, M. Gill, D. Morris, E. Quinn, T. W. Mühleisen, F. A. Degenhardt, et al. Manuel Mattheisen

  43:977-83.

  We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication studyWe conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.

• Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.

  Authors: P. Sklar, S. Ripke, L. J. Scott, O. A. Andreassen, S. Cichon, N. Craddock, H. J. Edenberg, J. I. Nurnberger, M. Rietschel, D. Blackwood [......] E. Scolnick, S. Djurovic, I. Melle, G. Morken, M. Gill, D. Morris, E. Quinn, T. W. Mühleisen, F. A. Degenhardt, Manuel Mattheisen et al

  43:977-83.

  We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication studyWe conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.