Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch

Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking.

Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring

Genome-wide association study identifies 30 loci associated with bipolar disorder

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 -4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10 -8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

eQTL effects for Systemic lupus erythematosus variants

<p>This is a companion figure for our 2015 American Society of Human Genetics poster. Here we show the genes for which we have evidence that they are regulated by variants associated to Systemic lupus erythematosus. We show clustering of these genes and functional enrichment per cluster. We also show that the regulation of some genes is context specific. For more details, you can download our poster here: http://broad.io/BIOSeQTL</p> <p> </p

Context-specific regulatory effects of genetic risk factors - ASHG 2015

<p>Using 2,116 whole blood RNA-seq samples, we have identified 10 modules that alter the effect of regulatory variants. These modules depict both celltype differences as well as cellular stimulations and were identified without any a priori knowledge on cell composition or perturbations.</p

eQTL effects for Celiac Disease variants

<p>This is a companion figure for our 2015 American Society of Human Genetics poster. Here we show the genes for which we have evidence that they are regulated by variants associated to Celiac Disease. We show clustering of these genes and functional enrichment per cluster. We also show that the regulation of some genes is context specific. For more details, you can download our poster here: http://broad.io/BIOSeQTL</p> <p> </p

eQTL effects for Rheumatoid Arthritis variants

<p>This is a companion figure for our 2015 American Society of Human Genetics poster. Here we show the genes for which we have evidence that they are regulated by variants associated to Rheumatoid Arthritis. We show clustering of these genes and functional enrichment per cluster. We also show that the regulation of some genes is context specific. For more details, you can download our poster here: http://broad.io/BIOSeQTL</p

eQTL effects for Multiple sclerosis variants

<p>This is a companion figure for our 2015 American Society of Human Genetics poster. Here we show the genes for which we have evidence that they are regulated by variants associated to eQTL effects for Multiple sclerosis variants. We show clustering of these genes and functional enrichment per cluster. We also show that the regulation of some genes is context specific. For more details, you can download our poster here: http://broad.io/BIOSeQTL</p

eQTL effects for Type 1 diabetes variants

<p>This is a companion figure for our 2015 American Society of Human Genetics poster. Here we show the genes for which we have evidence that they are regulated by variants associated to Type 1 diabetes. We show clustering of these genes and functional enrichment per cluster. We also show that the regulation of some genes is context specific. For more details, you can download our poster here: http://broad.io/BIOSeQTL</p