.2015 Feb 1:172:453-61.

doi: 10.1016/j.jad.2014.10.004. Epub 2014 Oct 12.

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

Kaya K Jacobsen¹, Caroline M Nievergelt², Tetyana Zayats³, Tiffany A Greenwood², Verneri Anttila⁴, Hagop S Akiskal⁵; BiGS Consortium; IHG Consortium; Jan Haavik⁶, Ole Bernt Fasmer⁷, John R Kelsoe⁵, Stefan Johansson⁸, Ketil J Oedegaard⁷

Collaborators, Affiliations

Collaborators

John R Kelsoe, Tiffany A Greenwood, Caroline M Nievergelt, Rebecca McKinney, Paul D Shilling, Erin N Smith, Nicholas J Schork, Cinnamon S Bloss, John I Nurnberger Jr, Howard J Edenberg, Tatiana Foroud, Daniel L Koller, Elliot S Gershon, Judith A Badner, Chunyu Liu, William A Scheftner, William B Lawson, Evaristus A Nwulia, Maria Hipolito, James Potash, William Coryell, John Rice, William Byerley, Francis J McMahon, Wade H Berrettini, Peter P Zandi, Pamela B Mahon, Melvin G McInnis, Sebastian Zöllner, Peng Zhang, David W Craig, Szabolics Szelinger, Thomas B Barrett, Thomas G Schulze, Juho Wedenoja, Mari A Kaunisto, Kauko Heikkilä, Jaakko Kaprio, Maija Wessman, Mikko Kallela, Markus Färkkilä, Ville Artto, Arpo Aromaa, Johan G Eriksson, Bendik S Winsvold, John-Anker Zwart, Padhraig Gormley, Aarno Palotie, Tobias Kurth, Lynda M Rose, Julie E Buring, Paul M Ridker, Daniel I Chasman, Francesco Bettella, Stacy Steinberg, Hreinn Stefansson, Kari Stefansson, George McMahon, George Davey-Smith, Rainer Malik, Tobias Freilinger, Heinz Erich Wichmann, Martin Dichgans, Bertram Muller-Myhsok, Thomas Meitinger, Boukje de Vries, Gisela Terwindt, Anine H Stam, Rune R Frants, Nadine Pelzer, Claudia M Weller, Ronald Zielman, Michel D Ferrari, Arn M J M van den Maagdenberg, Sarah E Medland, Grant W Montgomery, Nicholas G Martin, Dale R Nyholt, Unda Todt, Guntram Borck, Christian Kubisch, Lydia Quaye, Frances M K Williams, Lynn Cherkas, Markku Koiranen, Anna-Liisa Hartikainen, Anneli Pouta, Marjo-Riitta Jarvelin, M Arfan Ikram, Joyce van den Ende, Andre G Uitterlinden, Albert Hofman, Najaf Amin, Cornelia van Duijn, Terho Lehtimäki, Lannie Ligthart, Jouke-Jan Hottenga, Jacqueline M Vink, Brenda W Penninx, Dorret I Boomsma, Markus Schürks, Finnbogi Jakobsson, Jean Schoenen, Andrew C Heath, Pamela A F Madden, Hartmut Göbel, Axel Heinze, Katja Heinze-Kuhn, Stefan Schreiber, Verneri Anttila, Mark J Daly, Michael Alexander, Olli Raitakari, David P Strachan

Affiliations

¹ KG Jebsen Center for Neurophyciatric research, Department of Biomedicine, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. Electronic address: kja098@biomed.uib.no.
² Department of Psychiatry, University of California, San Diego, USA.
³ KG Jebsen Center for Neurophyciatric research, Department of Biomedicine, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
⁴ Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁵ Department of Psychiatry, University of California, San Diego, USA; Department of Psychiatry, VA Hospital, San Diego, USA.
⁶ KG Jebsen Center for Neurophyciatric research, Department of Biomedicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
⁷ KG Jebsen Center for Neurophyciatric research, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
⁸ KG Jebsen Center for Neurophyciatric research, Department of Biomedicine, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Norway.

PMID:25451450
PMCID: PMC4394021
DOI: 10.1016/j.jad.2014.10.004

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

Kaya K Jacobsen et al. J Affect Disord.2015.

.2015 Feb 1:172:453-61.

doi: 10.1016/j.jad.2014.10.004. Epub 2014 Oct 12.

Authors

Collaborators

John R Kelsoe, Tiffany A Greenwood, Caroline M Nievergelt, Rebecca McKinney, Paul D Shilling, Erin N Smith, Nicholas J Schork, Cinnamon S Bloss, John I Nurnberger Jr, Howard J Edenberg, Tatiana Foroud, Daniel L Koller, Elliot S Gershon, Judith A Badner, Chunyu Liu, William A Scheftner, William B Lawson, Evaristus A Nwulia, Maria Hipolito, James Potash, William Coryell, John Rice, William Byerley, Francis J McMahon, Wade H Berrettini, Peter P Zandi, Pamela B Mahon, Melvin G McInnis, Sebastian Zöllner, Peng Zhang, David W Craig, Szabolics Szelinger, Thomas B Barrett, Thomas G Schulze, Juho Wedenoja, Mari A Kaunisto, Kauko Heikkilä, Jaakko Kaprio, Maija Wessman, Mikko Kallela, Markus Färkkilä, Ville Artto, Arpo Aromaa, Johan G Eriksson, Bendik S Winsvold, John-Anker Zwart, Padhraig Gormley, Aarno Palotie, Tobias Kurth, Lynda M Rose, Julie E Buring, Paul M Ridker, Daniel I Chasman, Francesco Bettella, Stacy Steinberg, Hreinn Stefansson, Kari Stefansson, George McMahon, George Davey-Smith, Rainer Malik, Tobias Freilinger, Heinz Erich Wichmann, Martin Dichgans, Bertram Muller-Myhsok, Thomas Meitinger, Boukje de Vries, Gisela Terwindt, Anine H Stam, Rune R Frants, Nadine Pelzer, Claudia M Weller, Ronald Zielman, Michel D Ferrari, Arn M J M van den Maagdenberg, Sarah E Medland, Grant W Montgomery, Nicholas G Martin, Dale R Nyholt, Unda Todt, Guntram Borck, Christian Kubisch, Lydia Quaye, Frances M K Williams, Lynn Cherkas, Markku Koiranen, Anna-Liisa Hartikainen, Anneli Pouta, Marjo-Riitta Jarvelin, M Arfan Ikram, Joyce van den Ende, Andre G Uitterlinden, Albert Hofman, Najaf Amin, Cornelia van Duijn, Terho Lehtimäki, Lannie Ligthart, Jouke-Jan Hottenga, Jacqueline M Vink, Brenda W Penninx, Dorret I Boomsma, Markus Schürks, Finnbogi Jakobsson, Jean Schoenen, Andrew C Heath, Pamela A F Madden, Hartmut Göbel, Axel Heinze, Katja Heinze-Kuhn, Stefan Schreiber, Verneri Anttila, Mark J Daly, Michael Alexander, Olli Raitakari, David P Strachan

Affiliations

¹ KG Jebsen Center for Neurophyciatric research, Department of Biomedicine, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. Electronic address: kja098@biomed.uib.no.
² Department of Psychiatry, University of California, San Diego, USA.
³ KG Jebsen Center for Neurophyciatric research, Department of Biomedicine, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
⁴ Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁵ Department of Psychiatry, University of California, San Diego, USA; Department of Psychiatry, VA Hospital, San Diego, USA.
⁶ KG Jebsen Center for Neurophyciatric research, Department of Biomedicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
⁷ KG Jebsen Center for Neurophyciatric research, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
⁸ KG Jebsen Center for Neurophyciatric research, Department of Biomedicine, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Norway.

PMID:25451450
PMCID: PMC4394021
DOI: 10.1016/j.jad.2014.10.004

Abstract

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.

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.

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.

Keywords: Bipolar disorder; Genetics; Migraine; NBEA; Neurobeachin.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest: None of the authors report any conflict of interest.

Figures

**Figure 1**
Quantile-Quantile plot (QQ-plot) of observed and expected P-values, -log transformed. The genetic inflation factor (λ) was 1. The dashed horizontal line indicates a p-value of 5×10^-8. The grey shading indicates a 95% Confidence Interval.

**Figure 2**
Manhattan plot of results of logistical regression analyses. Chromosomes are pictured along the x-axis in alternating colors. −log10 P-values are plotted on y-axis. Red line indicates genome wide significance at 5×10^-8. A locus on chromosome 13 surpasses the threshold for genome wide significance.

**Figure 3**
LocusZoom plot of the candidate region on chromosome 13. Imputed SNPs are shown as circles, directly genotyped SNPs as diamonds. The color scheme indicates linkage disequilibrium (LD) structure across the region. The blue line indicates recombination rate. P-values are −log transformed. The top SNPs are in intronic regions of neurobeachin (*NBEA*). Rs1160720 is marked by a purple diamond (P-value 2.97×10^-8, OR: 1.82, 95% CI: 1.47-2.25).

See this image and copyright information in PMC

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

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

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