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dc.contributor.authorBahrami, Shahram
dc.contributor.authorHindley, Guy Frederick Lanyon
dc.contributor.authorWinsvold, Bendik K S
dc.contributor.authorO'Connell, Kevin S
dc.contributor.authorFrei, Oleksandr
dc.contributor.authorShadrin, Alexey
dc.contributor.authorCheng, Weiqiu
dc.contributor.authorBettella, Francesco
dc.contributor.authorRødevand, Linn
dc.contributor.authorØdegaard, Ketil Joachim
dc.contributor.authorFan, Chun C
dc.contributor.authorPirinen, Matti J
dc.contributor.authorHautakangas, Heidi M
dc.contributor.authorMartinsen, Amy
dc.contributor.authorSkogholt, Anne Heidi
dc.contributor.authorBrumpton, Ben Michael
dc.contributor.authorWiller, Cristen J
dc.contributor.authorTronvik, Erling Andreas
dc.contributor.authorKristoffersen, Espen Saxhaug
dc.contributor.authorZwart, John Anker Henrik
dc.contributor.authorNielsen, Jonas Bille
dc.contributor.authorHagen, Knut
dc.contributor.authorNilsen, Kristian Bernhard
dc.contributor.authorHveem, Kristian
dc.contributor.authorStovner, Lars Jacob
dc.contributor.authorFritsche, Lars
dc.contributor.authorThomas, Laurent
dc.contributor.authorPedersen, Linda Margareth
dc.contributor.authorGabrielsen, Maiken Elvestad
dc.contributor.authorJohnsen, Marianne Bakke
dc.contributor.authorLie, Marie
dc.contributor.authorHolmen, Oddgeir Lingaas
dc.contributor.authorBørte, Sigrid
dc.contributor.authorStensland, Synne
dc.contributor.authorZhou, Wei
dc.contributor.authorDale, Anders
dc.contributor.authorDjurovic, Srdjan
dc.contributor.authorSmeland, Olav Bjerkehagen
dc.contributor.authorAndreassen, Ole
dc.identifier.citationBrain. 2022, 145 (1), 142-153.en_US
dc.description.abstractMigraine is three times more prevalent in people with bipolar disorder or depression. The relationship between schizophrenia and migraine is less certain although glutamatergic and serotonergic neurotransmission are implicated in both. A shared genetic basis to migraine and mental disorders has been suggested but previous studies have reported weak or non-significant genetic correlations and five shared risk loci. Using the largest samples to date and novel statistical tools, we aimed to determine the extent to which migraine’s polygenic architecture overlaps with bipolar disorder, depression and schizophrenia beyond genetic correlation, and to identify shared genetic loci. Summary statistics from genome-wide association studies were acquired from large-scale consortia for migraine (n cases = 59 674; n controls = 316 078), bipolar disorder (n cases = 20 352; n controls = 31 358), depression (n cases = 170 756; n controls = 328 443) and schizophrenia (n cases = 40 675, n controls = 64 643). We applied the bivariate causal mixture model to estimate the number of disorder-influencing variants shared between migraine and each mental disorder, and the conditional/conjunctional false discovery rate method to identify shared loci. Loci were functionally characterized to provide biological insights. Univariate MiXeR analysis revealed that migraine was substantially less polygenic (2.8 K disorder-influencing variants) compared to mental disorders (8100–12 300 disorder-influencing variants). Bivariate analysis estimated that 800 (SD = 300), 2100 (SD = 100) and 2300 (SD = 300) variants were shared between bipolar disorder, depression and schizophrenia, respectively. There was also extensive overlap with intelligence (1800, SD = 300) and educational attainment (2100, SD = 300) but not height (1000, SD = 100). We next identified 14 loci jointly associated with migraine and depression and 36 loci jointly associated with migraine and schizophrenia, with evidence of consistent genetic effects in independent samples. No loci were associated with migraine and bipolar disorder. Functional annotation mapped 37 and 298 genes to migraine and each of depression and schizophrenia, respectively, including several novel putative migraine genes such as L3MBTL2, CACNB2 and SLC9B1. Gene-set analysis identified several putative gene sets enriched with mapped genes including transmembrane transport in migraine and schizophrenia. Most migraine-influencing variants were predicted to influence depression and schizophrenia, although a minority of mental disorder-influencing variants were shared with migraine due to the difference in polygenicity. Similar overlap with other brain-related phenotypes suggests this represents a pool of ‘pleiotropic’ variants that influence vulnerability to diverse brain-related disorders and traits. We also identified specific loci shared between migraine and each of depression and schizophrenia, implicating shared molecular mechanisms and highlighting candidate migraine genes for experimental validation.en_US
dc.publisherOxford University Pressen_US
dc.rightsNavngivelse-Ikkekommersiell 4.0 Internasjonal*
dc.titleDissecting the shared genetic basis of migraine and mental disorders using novel statistical toolsen_US
dc.title.alternativeDissecting the shared genetic basis of migraine and mental disorders using novel statistical toolsen_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US

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Navngivelse-Ikkekommersiell 4.0 Internasjonal
Except where otherwise noted, this item's license is described as Navngivelse-Ikkekommersiell 4.0 Internasjonal