Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder

Methods We performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS).Results We identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene (P=2.97×10-8, OR: 1.82, 95% CI: 1.47-2.25), although this was not replicated in a smaller sample of 289 migraine cases. Limitations Our study is based on self-reported migraine.Background Migraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine.Conclusions NBEA encodes neurobeachin, a scaffolding protein primarily expressed in the brain and involved in trafficking of vesicles containing neurotransmitter receptors. This locus has not previously been implicated in migraine per se. We found no evidence of association in data from the GWAS migraine meta-analysis consortium (n=118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder

Potent and broad HIV-neutralizing antibodies in memory B cells and plasma

Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. Antibody 10E8, reactive with the distal portion of the membrane-proximal external region (MPER) of HIV-1 gp41, is broadly neutralizing. However, the ontogeny of distal MPER antibodies and the relationship of memory B cell to plasma bnAbs are poorly understood. HIV-1–specific memory B cell flow sorting and proteomic identification of anti-MPER plasma antibodies from an HIV-1–infected individual were used to isolate broadly neutralizing distal MPER bnAbs of the same B cell clonal lineage. Structural analysis demonstrated that antibodies from memory B cells and plasma recognized the envelope gp41 bnAb epitope in a distinct orientation compared with other distal MPER bnAbs. The unmutated common ancestor of this distal MPER bnAb was autoreactive, suggesting lineage immune tolerance control. Construction of chimeric antibodies of memory B cell and plasma antibodies yielded a bnAb that potently neutralized most HIV-1 strains

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

Lithium-responsive genes and gene networks in bipolar disorder patient-derived lymphoblastoid cell lines

Lithium (Li) is the mainstay mood stabilizer for the treatment of bipolar disorder (BD), although its mode of action is not yet fully understood nor is it effective in every patient. We sought to elucidate the mechanism of action of Li and to identify surrogate outcome markers that can be used to better understand its therapeutic effects in BD patients classified as good (responders) and poor responders (nonresponders) to Li treatment. To accomplish these goals, RNA-sequencing gene expression profiles of lymphoblastoid cell lines (LCLs) were compared between BD Li responders and nonresponders with healthy controls before and after treatment. Several Li-responsive gene coexpression networks were discovered indicating widespread effects of Li on diverse cellular signaling systems including apoptosis and defense response pathways, protein processing and response to endoplasmic reticulum stress. Individual gene markers were also identified, differing in response to Li between BD responders and nonresponders, involved in processes of cell cycle and nucleotide excision repair that may explain part of the heterogeneity in clinical response to treatment. Results further indicated a Li gene expression signature similar to that observed with clonidine treatment, an α2-adrenoceptor agonist. These findings provide a detailed mechanism of Li in LCLs and highlight putative surrogate outcome markers that may permit for advanced treatment decisions to be made and for facilitating recovery in BD patients.</p

Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder

Mechanisms of disease, diagnostics and therap

A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression

Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and the results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n = 359). We found 80 single-nucleotide polymorphisms (SNPs) with false discovery rate &lt;&nbsp;0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P &lt; 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI-treated patients with major depressive disorder: the MARS (n = 253, P = 0.0169) and GENDEP studies (n = 432, P = 0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal-related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TFs. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response

Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder

Methods We performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS)

Genome-Wide Association Analysis of Age at Onset and Psychotic Symptoms in Bipolar Disorder

Genome-wide association studies (GWAS) have identified several susceptibility loci for bipolar disorder (BP), most notably ANK3. However, most of the inherited risk for BP remains unexplained. One reason for the limited success may be the genetic heterogeneity of BP. Clinical sub-phenotypes of BP may identify more etiologically homogeneous subsets of patients, which can be studied with increased power to detect genetic variation. Here, we report on a mega-analysis of two widely studied sub-phenotypes of BP, age at onset and psychotic symptoms, which are familial and clinically significant. We combined data from three GWAS: NIMH Bipolar Disorder Genetic Association Information Network (GAIN-BP), NIMH Bipolar Disorder Genome Study (BiGS), and a German sample. The combined sample consisted of 2,836 BP cases with information on sub-phenotypes and 2,744 controls. Imputation was performed, resulting in 2.3 million SNPs available for analysis. No SNP reached genome-wide significance for either sub-phenotype. In addition, no SNP reached genome-wide significance in a meta-analysis with an independent replication sample. We had 80% power to detect associations with a common SNP at an OR of 1.6 for psychotic symptoms and a mean difference of 1.8 years in age at onset. Age at onset and psychotic symptoms in BP may be influenced by many genes of smaller effect sizes or other variants not measured well by SNP arrays, such as rare alleles