Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Hou, Liping; Bergen, Sarah E.; Akula, Nirmala; Song, Jie; Hultman, Christina M.; Landén, Mikael; Adli, Mazda; Alda, Martin; Ardau, Raffaella; Arias, Bárbara; Aubry, Jean Michel; Backlund, Lena; Badner, Judith A.; Barrett, Thomas B.; Bauer, Michael; Baune, Bernhard T.; Bellivier, Frank; Benabarre, Antonio; Bengesser, Susanne; Berrettini, Wade H.; Bhattacharjee, Abesh Kumar; Biernacka, Joanna M.; Birner, Armin; Bloss, Cinnamon S.; Brichant‐Petitjean, Clara; Bui, Elise; Byerley, William; Cervantes, Pablo; Chillotti, Caterina; Cichon, Sven; Colom, Francesc; Coryell, William; Craig, David W.; Cruceanu, Cristiana; Czerski, Piotr M.; Davis, Tony; Dayer, Alexandre; Degenhardt, Franziska; Zompo, Maria Del; DePaulo, J. Raymond; Edenberg, Howard J.; Étain, Bruno; Falkai, Peter; Foroud, Tatiana; Forstner, Andreas J.; Frisén, Louise; Frye, Mark A.; Fullerton, Janice M.; Gard, Sébastien; Garnham, Julie; Gershon, Elliot S.; Goes, Fernando S.; Greenwood, Tiffany A.; Grigoroiu‐Serbanescu, Maria; Hauser, Joanna; Heilbronner, Urs; Herms, Stefan; Hipolito, Maria; Hitturlingappa, Shashi; Hoffmann, Per; Hofmann, Andrea; Jamain, Stéphane; Jiménez, Esther; Kahn, Jean Pierre; Kassem, Layla; Kelsoe, John R.; Kittel‐Schneider, Sarah; Kliwicki, Sebastian; Koller, Daniel L.; König, Barbara; Lackner, Nina; Laje, Gonzalo; Lang, Maren; Lavebratt, Catharina; Lawson, William B.; Leboyer, Marion; Leckband, Susan G.; Liu, Chun Yu; Maaser, Anna; Mahon, Pamela B.; Maier, Wolfgang; Maj, Mario; Manchia, Mirko; Martinsson, Lina; McCarthy, Michael J.; McElroy, Susan L.; McInnis, Melvin G.; McKinney, R. Anne; Mitchell, Philip B.; Mitjans, Marina; Mondimore, Francis M.; Monteleone, Palmiero; Mühleisen, Thomas W.; Nievergelt, Caroline M.; Nöthen, Markus M.; Novák, Tomáš; Nürnberger, John I.; Nwulia, Evaristus; Ösby, Urban; Pfennig, Andrea; Potash, James B.; Propping, Peter; Reif, Andreas; Reininghaus, Eva; Rice, John P.; Rietschel, Marcella; Rouleau, Guy A.; Rybakowski, Janusz; Schalling, Martin; Scheftner, William A.; Schofield, Peter R.; Schork, Nicholas J.; Schulze, Thomas G.; Schumacher, Johannes; Schweizer, Barbara; Severino, Giovanni; Shekhtman, Tatyana; Shilling, Paul D.; Simhandl, Christian; Slaney, Claire; Smith, Erin N.; Squassina, Alessio; Stamm, Thomas; Stopková, Pavla; Streit, Fabian; Strohmaier, Jana; Szelinger, Szabolcs; Tighe, Sarah K.; Tortorella, Alfonso; Turecki, Gustavo; Vieta, Eduard; Volkert, Julia; Witt, Stephanie H.; Wright, Adam; Zandi, Peter P.; Zhang, Peng; Zöllner, Sebastian; McMahon, Francis J.

doi:10.1093/hmg/ddw181

Cited by 193 publications

(155 citation statements)

References 63 publications

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“…This SNP did not show genome-wide significance in the following GWAS [12, 15, 17-19], raising the need for further replication analyses. In our Han Chinese case-control sample, while rs1064395 did not achieve the conventional nominal significance ( p = 0.415, OR = 1.070 for the A allele, Table 1), the direction of allelic effect was the same as those in European studies.…”

Section: Resultsmentioning

confidence: 99%

“…The single nucleotide polymorphism (SNP) rs1064395 in NCAN was found to be genome-wide significantly associated with BPD in a GWAS plus replication analysis in a total of 8,441 cases and 35,362 controls by Cichon et al [13] ( p = 2.14 × 10 –9 ). However, this SNP did not reach genome-wide significance in other BPD GWAS [15, 17-19], which may be the result of genetic background heterogeneity among different samples. However, a potential impact of rs1064395 on the risk of BPD was supported by its associations with brain function, cognitive performance, and risk of other psychiatric disorder (i.e., schizophrenia) [23-27].…”

Section: Introductionmentioning

confidence: 84%

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Further Evidence of an Association between NCAN rs1064395 and Bipolar Disorder

Wang

Liu

et al. 2018

Complex Psychiatry

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Genome-wide association studies suggest that rs1064395 in the neurocan gene (NCAN) is a potential risk factor for bipolar disorder (BPD), and further replication analyses in larger independent samples are needed. We herein analyzed rs1064395 in a Han Chinese sample of 1,146 BPD cases and 2,031 controls, followed by a meta-analysis of BPD samples from worldwide populations including a total of 15,318 cases and 91,990 controls. The meta-analysis found that rs1064395 showed a genome-wide significant association with BPD (p = 4.92 × 10^–9, OR = 1.126 for the A allele), although it did not reach the significance level in the Han Chinese sample (p = 0.415, OR = 1.070 for the A allele). We also examined the association between the single nucleotide polymorphisms and major depressive disorder (MDD) given the presumed genetic overlap between BPD and MDD, and rs1064395 was also associated with MDD (p = 0.0068, OR = 1.067 for the A allele) in a meta-analysis of 14,543 cases and 14,856 controls. Our data provide further evidence for the involvement of NCAN in the genetic susceptibility to BPD and also implicate its broader role in major mood disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 84%

Further Evidence of an Association between NCAN rs1064395 and Bipolar Disorder

Wang

Liu

et al. 2018

Complex Psychiatry

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“…The number of significant common single nucleotide polymorphism (SNP) associations detected in GWAS should rise as sample sizes increase. Recently, two novel loci associated with BD have been identified in the GWAS of 40 000 individuals …”

Section: Geneticsmentioning

confidence: 99%

Biological hypotheses and biomarkers of bipolar disorder

Sigitova

Fišar

Hroudová

et al. 2017

Psychiatry Clin Neurosci

192

117

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The most common mood disorders are major depressive disorders and bipolar disorders (BD). The pathophysiology of BD is complex, multifactorial, and not fully understood. Creation of new hypotheses in the field gives impetus for studies and for finding new biomarkers for BD. Conversely, new biomarkers facilitate not only diagnosis of a disorder and monitoring of biological effects of treatment, but also formulation of new hypotheses about the causes and pathophysiology of the BD. BD is characterized by multiple associations between disturbed brain development, neuroplasticity, and chronobiology, caused by: genetic and environmental factors; defects in apoptotic, immune-inflammatory, neurotransmitter, neurotrophin, and calcium-signaling pathways; oxidative and nitrosative stress; cellular bioenergetics; and membrane or vesicular transport. Current biological hypotheses of BD are summarized, including related pathophysiological processes and key biomarkers, which have been associated with changes in genetics, systems of neurotransmitter and neurotrophic factors, neuroinflammation, autoimmunity, cytokines, stress axis activity, chronobiology, oxidative stress, and mitochondrial dysfunctions. Here we also discuss the therapeutic hypotheses and mechanisms of the switch between depressive and manic state.

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“…A tremendous effort has been expended into GWAS of SZ [77] and BD [78], and it is recognized that there is a large number of common variants contributing to the polygenic susceptibility for these disorders. Estimates from several hundred genes of small effect size, as published in the largest international genetic study of SZ [79], to the possibility that thousands of genes are involved in the pathogenesis of SZ were made [80].…”

Section: Discussionmentioning

confidence: 99%

Exon Array Biomarkers for the Differential Diagnosis of Schizophrenia and Bipolar Disorder

et al. 2017

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This study developed potential blood-based biomarker tests for diagnosing and differentiating schizophrenia (SZ), bipolar disorder type I (BD), and normal control (NC) subjects using mRNA gene expression signatures. A total of 90 subjects (n = 30 each for the three groups of subjects) provided blood samples at two visits. The Affymetrix exon microarray was used to profile the expression of over 1.4 million probesets. We selected potential biomarker panels using the temporal stability of the probesets and also back-tested them at two different visits for each subject. The 18-gene biomarker panels, using logistic regression modeling, correctly differentiated the three groups of subjects with high accuracy across the two different clinical visits (83–88% accuracy). The results are also consistent with the actual data and the “leave-one-out” analyses, indicating that the models should be predictive when applied to independent data cohorts. Many of the SZ and BD subjects were taking antipsychotic and mood stabilizer medications at the time of blood draw, raising the possibility that these drugs could have affected some of the differential transcription signatures. Using an independent Illumina data set of gene expression data from antipsychotic medication-free SZ subjects, the 18-gene biomarker panels produced a receiver operating characteristic curve accuracy greater than 0.866 in patients that were less than 30 years of age and medication free. We confirmed select transcripts by quantitative PCR and the nCounter® System. The episodic nature of psychiatric disorders might lead to highly variable results depending on when blood is collected in relation to the severity of the disease/symptoms. We have found stable trait gene panel markers for lifelong psychiatric disorders that may have diagnostic utility in younger undiagnosed subjects where there is a critical unmet need. The study requires replication in subjects for ultimate proof of the utility of the differential diagnosis.

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Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Cited by 193 publications

References 63 publications

Further Evidence of an Association between <b><i>NCAN</i></b> rs1064395 and Bipolar Disorder

Further Evidence of an Association between <b><i>NCAN</i></b> rs1064395 and Bipolar Disorder

Biological hypotheses and biomarkers of bipolar disorder

Exon Array Biomarkers for the Differential Diagnosis of Schizophrenia and Bipolar Disorder

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