MAP1B mutations cause intellectual disability and extensive white matter deficit

Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Discovery of coding variants in genes that confer risk of neurodevelopmental disorders is an important step towards understanding the pathophysiology of these disorders. Wholegenome sequencing of 31,463 Icelanders uncovers a frameshift variant (E712KfsTer10) in microtubule-associated protein 1B (MAP1B) that associates with ID/low IQ in a large pedigree (genome-wide corrected P = 0.022). Additional stop-gain variants in MAP1B (E1032Ter and R1664Ter) validate the association with ID and IQ. Carriers have 24% less white matter (WM) volume (β = −2.1SD, P = 5.1 × 10−8), 47% less corpus callosum (CC) volume (β = −2.4SD, P = 5.5 × 10−10) and lower brain-wide fractional anisotropy (P = 6.7 × 10−4). In summary, we show that loss of MAP1B function affects general cognitive ability through a profound, brain-wide WM deficit with likely disordered or compromised axons.We are grateful to the participants and we thank the psychologists, nurses and staff, in particular Berglind Eiriksdottir, at the Research Recruitment Center and technicians and staff at Röntgen Domus. We also thank the staff at deCODE genetics core facilities and all our colleagues for their important contribution to this work. L.J. received support from the Swedish Society of Medicine, the Swedish Brain Foundation and Swedish Society for Medical Research. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreements’ no. 115008 (NEWMEDS) and no. 115300 (EUAIMS) of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (EU-FP7/2007-2013), EU-FP7 funded grant no. 602450 (IMAGEMEND) and EU funded FP7-People-2011-IAPP grant agreement no. 286213 (PsychDPC).Peer Reviewe

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Publisher Copyright: © 2023, The Author(s).Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.Peer reviewe

Erfðafræði taugaþroskaraskana Áhrif sjaldgæfra breytileika á byggingu og starfsemi heilans

Introduction and aims: Development of the nervous system is a complex and highly regulated process that, when impaired, can result in a multitude of disorders of varying behavioural, cognitive, and functional severity. Variation in brain structure and function is considered causal in neurodevelopmental and psychiatric disorders. However, these disorders are not, nosologically, defined by evident, or at least consistently replicated, neuropathology, and the underlying biological mechanisms are largely unknown. Autism spectrum disorder (ASD), intellectual disability (ID), learning disorders and attention deficit/hyperactivity disorder (ADHD) are increasingly prevalent, childhood onset disorders with diverse phenotypic presentation and etiology. These disorders co-occur frequently, with research in recent years revealing evidence for shared risk factors and genetic studies providing novel insights into the pathogenesis and biochemical pathways perturbed in these disorders. Four studies form the basis of the work described in this thesis where novel associations with neurodevelopmental disorders (NDDs) are described as well as how the sequence variants impact cognition and brain structure and function. The aim of the research was to increase understanding of the etiology of NDDs, improve detection and diagnosis that might bolster treatment and support personalised medicine. This is of particular interest for the NDDs due to their early onset and heterogeneous nature but more significantly the importance to intervene with treatments as early as possible to improve treatment success and quality of life. Methods: Single nucleotide polymorphism (SNP) chip array genotyping, followed by data analysis with the PENN-CNV algorithm, allowed identification of individuals carrying copy number variations, that have previously been associated with ASD and schizophrenia. Inidividual carriers, without a diagnosis of ASD or schizophrenia were offered participation. For the final study (paper IV) whole genome sequencing (WGS) was applied and all coding variants identified for analysis. Firstly, a battery of tests gauging various cognitive domains, previously observed to be impaired in schizophrenia or ASD, were applied. These include attention, spatial working memory, logical memory, executive function, cognitive flexibility, language, processing speed and emotion recognition. The intelligence quotient, was also estimated, using Wechslers scale of intelligence and subjects asked about learning difficulties (reading and mathematics), daily functioning and a short psychiatric evaluation was performed. Statistical analyses used a generalised least-squares regression with a variance-covariance matrix based on the kinship coefficient of each pair of individuals and multiple comparisons were accounted for using a Bonferroni correction to set appropriate P-value threshold. Second, magnetic resonance imaging (MRI) was used to collect structural images of the brain subsequently segmented into white matter (WM), grey matter (GM) and cerebrospinal fluid using standard methods (Statistical Parametric Mapping, SPM8 software) to examine voxel-based morphometry (VBM), in the Matlab platform, by analysing regional brain volumes (in regions of interest; ROI) on a voxel-by-voxel basis with a multiple regression model. Brain-wide surface-based morphometry (SBM) of the image data was also performed with FreeSurfer which segments and parcellates regions according to predefined atlases into volumes, surface areas and thickness values and generalised least-squares regression used to analyse the date. Third, functional MRI data were also collected from a subset of the structural MRI sample. The functional MRI consisted of two paradigms, a phonological lexical decision task, based on published methods, and a multiplication verification task. Broadly, in the word task participants were asked to decide whether a visually presented letter string sounded like a real word or not and for the multiplication task participants were asked to verify whether a visually presented multiplication equation was correct or not. The functional MRI data was handled with validated methods and statistically analysed using SPM12. Based on results from the structural MRI and a prior hypothesis, a mask was generated which focuses the analysis on specific regions. Fourth, diffusion tensor image data were also acquired and pre-processed using the Functional Magnetic Resonance Imaging of the Brain Software Library. Using tract-based spatial statistics (TBSS) voxel-wise statistical analysis of the fractional anisotropy (FA) data was performed. Multiple regression models were used to investigate the effect of carrier status on FA. Results: Paper I. CNVs repesent an important part of the sequence diversity of the human genome and CNVs in many regions have been identified as harbouring risk factors for NDDs and psychiatric disorders. From the literature 26 CNVs were identified, referred to as neuropsych CNV alleles, that have been associated with schizophrenia and/or ASD, and carriers of these alleles offered participation in a study that gauges cognitive ability on a range of aptitude tests. Results revealed that carrying one of these CNVs incurs a disadvantage in the form of cognitive impairment; with the 16p11.2 proximal deletion, 17p12 deletion and 16p13.11 duplication showing the strongest overall association with verbal and/or performance IQ impairment. While the 15q11.2(BP1-BP2) deletion shows modest impairments on the neuropsychological tests it is strongly associated with a history of difficulties in learning to read (dyslexia) and mathematics (dyscalculia), even after accountig for IQ. Participants in the study also had scans of their brain applying structural MRI in search of neural intermediate phenotypes. As a consequence of these results and the previously identified association with schizophrenia, the 15q11.2(BP1-BP2) CNV carriers were examined with MRI and, based on ROI analyses of the MRI data defined by a recent meta-analysis of first-episode psychosis, it was found that the deletion carriers have a reduced volume of GM in the perigenual anterior cingulate cortex and the left insula. Furthermore, deletion carriers showed reductions in WM of the temporal lobe, bilaterally, and an increase in the volume of the corpus callosum (CC). 15q11.2(BP1-BP2) duplication carriers showed reciprocal changes in the same regions altered in deletion carriers for both GM and WM. Most of the CNVs tested showed lower fecundity, strongest effect shown by 16p11.2 proximal deletion and 22q11.21 duplication, especially in males. This supports the observation that many of these recurrent sequence variants are under negative selection. Paper II. A larger, hypothesis free, follow-up study showed that the 15q11.2(BP1-BP2) deletion associates with an increased WM volume of the anterior CC and decreased GM in left fusiform gyrus and left angular gyrus. Using tailored functional MRI paradigms, phonological lexical decision and multiplication verification tasks, decreased activation in the left fusiform and the left angular gyri were observed in deletion carriers. While brain regions showed reciprocal (mirrored) changes between 15q11.2(BP1-BP2) deletion and duplication carriers, cognitive abilities did not. Furthermore, variations in cognitive test scores and brain imaging phenotypes did not significantly correlate, most likely due to a decrease in power to detect such an effect from modest overlap of cognitive assessment and MRI. Paper III. Of the 26 CNVs discussed in paper I, 19 were considered to fulfill the claim of significant association with ASD or schizophrenia. Fourteen had power to be tested for association, and eight exhibited significant association with ADHD. Association with two CNVs has been reported previously, 16p13.11 duplication and 22q11.21 deletion, but associations with the remaining six are novel, deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5-BP5), and duplications at 1q21.1 distal, 16p11.2 proximal, and 22q11.21, although an increased frequency of ADHD in carriers has been reported for some. As a group, the 19 CNVs associate significantly with ADHD, even when co-occurring ASD and schizophrenia were excluded from the sample. Paper IV. Applying family-based analysis to WGS data, testing rare coding-sequence variants for segregation with ID and lowered IQ, uncovered three loss of function (LoF) variants in the microtubule-associated protein 1B (MAP1B) gene in three separate Icelandic pedigrees. Structural MRI, of MAP1B LoF carrier brains, revealed significantly lower brain wide WM volume with considerable deficit in the CC. TBSS analysis applied to whole-brain diffusion data revealed an association with reduced FA in brain-wide WM tracts in MAP1B LoF carriers. Clinical assessment of the MRI also showed periventricular nodular heterotopia in nine of the ten MAP1B LoF carriers. Functional studies, where plasmids expressing MAP1B protein that has incorporated each of the LoF mutations, showed that truncated MAP1B protein is stable. Conclusions: NDDs and psychiatric disorders can be debilitating conditions for those affected. Changes in cognition are an integral part of these disorders and intellectual impairment a confounding factor in their presentation. To study the cognitive element, independent of the clinical state, we identified carriers of sequence variants, that confer risk of NDDs and psychiatric disorders, yet do not have a diagnosis of those disorders. These individuals were administered a battery of cognitive tests and brain MRI that establish specific cognitive impairments and structural changes akin to those diagnosed with schizophrenia. This led us to propose that the cognitive impairments are not necessarily consequences of the disorders they accompany but may in fact mediate some of the disorder risk instead. Using those same tools, we identified an association between a CNV and specific learning disorders, independent of IQ, and structural and functional changes in the brain previously identified as being important for reading and arithmetic. We also discovered protein truncating variants that associate strongly with intellectual impairments and dramatic changes in brain WM. The results we present broadening the impact of the Neuropsych CNVs to include risk of ADHD, highlights the pleiotropic effects of these CNVs but also adds to the evidence that the NDDs and psychiatric disorders are related rather than etiologically distinct entities. The examples above demonstrate the advantage of applying genetics to tease apart confounding traits and provides an avenue for studying the connection between neurological changes and cognition.Inngangur og markmið: Þroskunarferli taugakerfisins er flókið kerfi, undir nákvæmri stjórn, og truflanir geta leitt til mismunandi raskana á hegðun eða vitrænni starfsemi. Talið er að orsakasamhengi sé á milli breytinga í byggingu heilans og virkni hans, sem og taugaþroska- og geðraskana. Þó eru raskanir ekki skilgreindar á grundvelli slíkra breytinga og undirliggjandi líffræðilegir þættir og ferli eru að mestu leyti óþekkt. Röskun á einhverfurófi, skert greind, námsraskanir, og athyglisbrestur/ofvirkniröskun eru sífellt algengari raskanir, sem oft fylgjast að og verður yfirleitt vart við í æsku. Rannsóknir undanfarinna ára benda til sameiginlegra erfðafræðilegra áhættuþátta. Í erfðamenginu er hægt að greina kirnabreytileika með raðgreiningu og suma eintakabreytileika með örflöguskimun, og breytileikar í erfðamengi hafa verið tengdir við taugaþroskaraskanir og geðraskanir með víðtækri erfðamengisskimun. Fjórar rannsóknir liggja til grundvallar þessari ritgerð, þar sem áhrifum breytileika í erðamenginu á vitsmuni, byggingu og virkni heilans er lýst. Markmið rannsóknarinnar er að dýpka skilning á orsökum taugaþroskaraskana, sem gæti varðað leiðina að bættri greiningu og einstaklingsmiðaðri meðferð. Aðferðir: Með því að arfgerðagreina einstaklinga, með kirnabreytileika á örflögum og beita svo PENN-CNV algrími á gögnin, fundust arfberar eintakabreytileika. Meðal arfbera eintakabreytileika sem tengdir hafa verið við áhættu á einhverfurófsröskun og geðklofa, var einstaklingum sem ekki hafa fengið slíkar greiningar boðin þátttaka í rannsókninni. Fyrir lokarannsóknina (vísindagrein IV), var erfðamengisraðgreiningu beitt og þeir kirnabreytileikar í kóðunarröðum sem fundust voru auðkenndir til frekari greiningar. Þátttakendur leystu verkefni sem mæla ýmis vitsmunasvið, svo sem athygli, rýmisvinnsluminni, rökhugsun, hugræna stýriferla (e. executive function), sveigjanleika í hugsun, tungumálaskilning, vinnsluhraða og tilfinninganæmi. Greindarvísitala (IQ) var mæld með Wechsler-skala og spurt um sértæka námsörðugleika (lestur og stærðfræði), getu í daglegum athöfnum og svo var lagt mat á geðheilsu og andlegt ástand með stuttu sálfræðiviðtali. Tölfræðivinnsla fór fram með aðhvarfsgreiningu (generalised least-squares regression) með fylgibreytu sem tekur mið af skyldleika þátttakenda. Marktækni var metin með því að leiðrétta fyrir fjölda prófa og var hún miðuð við Bonferroni þröskuld. iv Segulómun var notuð til að safna myndum af heilum þátttakenda og myndirnar sundur liðaðar eftir svæðum í hvítt efni, grátt efni og mænuvökva. Stöðluðum aðferðum (SPM8) var beitt til að lýsa formi og byggingu heilans með stöðluðum rúmeiningum (voxel-based morphometry) með Matlab-forriti sem gerir kleift að meta rúmmál ákveðinna heilasvæða og rannsaka fylgni milli samantekta á rúmeiningunum og arfgerðar með aðhvarfsgreiningu (multiple regression model). Formgreining á yfirborði svæða og þykkt þeirra (surface-based morphometry) var einnig framkvæmd. Enn fremur var notast við FreeSurfer-hugbúnað, sem finnur og greinir fyrir fram skilgreind svæði og gefur þeim rúmmáls-, yfirborðsflatarmáls- og þykktargildi sem síðan voru notuð í aðhvarfsgreiningu. Starfrænum segulómunargögnum var einnig safnað. Tvö starfræn verkefni voru lögð fyrir, eitt sem reynir á lesskilning, þar sem þátttakendur voru beðnir að ákveða hvort orð sem birtist á skjánum hljómaði eins og alvöru orð eða ekki, og annað sem prófar margföldunarskilning, þar sem þátttakendur lögðu mat á hvort lausn á margföldunardæmi væri rétt. Gögnin voru meðhöndluð með birtum aðferðum og tölfræðilega greind með SPM12. Rannsóknin var byggð á niðurstöðum úr segulómun, þar sem einungis voru skoðuð fyrir fram ákveðin svæði. Þinflæðismyndgreining (diffusion tensor imaging) var einnig beitt til að kortleggja taugabrautir í heila þátttakenda. Myndgögn voru forunnin með FMRIB hugbúnaðarsafninu. Mæling á því að hvaða leyti flæði (diffusion) stefnuhneigð (fractional anisotropy) var metin með rúmeiningalíkani og aðhvarfsgreiningu (multiple regression model). Niðurstöður: Grein I. Tuttugu og sex eintakabreytileikar, sem hafa áður verið tengdir við taugaþroskaraskanir og geðklofa (kallaðir Neuropsych CNVs), voru valdir. Sýnt var fram á það að arfberar slíkra eintakabreytileika standa sig verr á ýmsum vitsmunaprófum. Þeir sem bera 16p11.2 nær (proximal) brottfellingu, 17p12 brottfellingu eða 16p13.11 tvöföldun, sýndu sterkustu tengslin við skerðingu á munnlegri og/eða verklegri greind. 15q11.2(brotsvæði 1-2) brottfellingin sýndi lítil tengsl við greindarskerðingu en sterk tengsl við sértæku námsörðugleikana lesblindu (dyslexiu) og reikniblindu/talnablindu (dyscalculia). Þátttakendur voru myndaðir með segulómun til að skoða byggingu heilans. Þar sem 15q11.2(brotsvæði 1-2) brottfellingin hefur áður verið tengd við geðklofa voru svæði áður tengd geðklofa skoðuð hjá þeim sem bera brottfellinguna en eru ekki með geðklofagreiningu. Í ljós kom að þessir einstaklingar eru með breytingar sambærilegar þeim sem greinast með geðklofa; minnkað rúmmál gráa efnis í framhluta gyrðilberkis (perigenual anterior cingulate cortex) og vinstra eyjarblaði (insula), minna rúmmál hvíta efnis gagnaugablaðs (temporal lobe), í báðum heilahvelum, og aukið rúmmál af hvíta efni hvelatengslana (corpus callosum), sem tengir heilahvelin. Það sem ekki hefur verið v sýnt fram á áður er að þeir sem bera gagnkvæma eintakabreytileikann, 15q11.2(brotsvæði 1-2) tvöföldunina, sýna gagnstæð áhrif á sömu svæði og sýna breytingar í arfberum brottfellingarinnar. Niðurstaðan bendir til skammtaáhrifa erfðavísana sem eru á þessu litningasvæði. Flestir þessara eintakabreytileika hafa áhrif á frjósemi, sem skilgreind var sem fjöldi barna arfbera fyrir 45 ára aldur þar sem að sterkustu áhrifin fylgja 16p11.2 nær (proximal) brottfellingunni og 22q11.21 tvöfölduninni, sérstaklega hjá körlum. Það styður þá kenningu að þessir eintakabreytileikar séu undir neikvæðu vali. Grein II. Í stærri framhaldsrannsókn þar sem allur heilinn var rannsakaður, var sýnt að 15q11.2(brotsvæði 1-2) brottfellingin tengist auknu rúmmáli hvíta efnis í framhluta tengihvels (anterior corpus callosum) og minnkuðu rúmmáli gráa efnis í vinstri spólugára (left fusiform gyrus) og vinstri horngára (left angular gyrus). Starfræn segulómun leiddi í ljós minni virkni í vinstri spólugára í lesskilningsverkefni, og minni virkni í vinstri horngára í margföldunarverkefni hjá þeim sem bera 15q11.2(brotsvæði 1-2) brottfellinguna. Breytingar í spólugára hafa verið tengdar við lesskilning og breytingar í horngára við talnaskilning. Í fyrri rannsókn var sýnt fram á gagnkvæmar (speglaðar) breytingar í heilasvæðum á milli 15q11.2(brotsvæði 1-2) brottfellingarbera og tvöföldunarbera, en slíka speglun var ekki að sjá á vitsmunaprófum. Jafnframt var engin marktæk fylgni á milli prófskora og heilabreytna, sem kann að skýrast af litlu tölfræðilegu afli til að finna tengsl vegna smæðar hópsins. Grein III. Af þeim 26 eintakabreytileikum sem fjallað var um í grein I þá voru 19 enn þá taldir uppfylla skilyrðið fyrir marktækri fylgni við einhverfurófsröskun eða geðklofa. Fjórtán voru með nægjanlegt tölfræðiafl til að prófa og átta voru marktækt tengdir ADHD. Tengslum við tvo þeirra hefur þegar verið lýst í birtum vísindagreinum, við 16p13.11 tvöföldunina og 22q11.21 brottfellinguna, en tengsl við hina sex eru ný, brottfellingar í 2p16.3 (NRXN1), 15q11.2 og 15q13.3 (BP4 & BP4.5-BP5), og tvöfaldanir á 1q21.1 fjær (distal), 16p11.2 (nær) proximal, og 22q11.21. Sem hópur, sýndu allir 19 eintakabreytileikarnir marktæka fylgni við ADHD, jafnvel eftir að einstaklingar með einhverfurófsröskun eða geðklofa voru fjarlægðir úr þýðinu. Grein IV. Greining á fylgni sjaldgæfra kirnabreytileika í kóðunarröðum við greindarskerðingu eða lága greind, innan fjölskyldna, bar kennsl á þrjá breytileika sem valda styttingu á próteinafurð MAP1B erfðavísisins í þremur íslenskum fjölskyldum. Segulómun á heilum arfbera þessa kirnabreytileika sýndi verulega minnkun á hvíta efni heilans, sérstaklega hvelatengslana. Þinflæðisgreining benti til víðtækrar lækkunar á stefnuhneigð (fractional anisotropy) í öllum hvíta efnis brautum heilans. Klínískt mat á segulómsgögnunum leiddi í ljós hnúða í vi heilahólfunum (periventricular nodular heterotopia) í níu af tíu berum þessara breytileika. Rannsókn, þar sem plasmíð eru notuð til að tjá útgáfur af MAP1B geninu með þessa þrjá kirnabreytileika, sýndi að stuttar útgáfur af próteininu geta verið stöðugar. Ályktanir: Taugaþroskaraskanir og geðraskanir geta verið mjög hamlandi. Greindarskerðing, sem stundum er samfara þessum röskunum, getur truflað greiningu þeirra. Til að einangra og rannsaka vitræna þáttinn voru valdir arfberar eintakabreytileika, sem auka áhættu á einhverfurófsröskun eða geðklofa, en hafa ekki fengið greiningu á þessum röskunum. Ýmis vitræn próf voru lögð fyrir þessa einstaklinga og heilar þeirra kannaðir með segulómun. Rannsóknin leiddi í ljós sértækar greindarskerðingar og heilabreytingar sem svipar til þeirra sem eiga sér stað hjá þeim sem greinast með geðklofa. Út frá þessum niðurstöðum spratt sú tilgáta að breytingar á vitsmunum séu ekki endilega afleiðing geðraskana, heldur geti þær jafnvel miðlað hluta af sjúkdómsáhættunni. Sömu rannsóknaraðferðir voru notaðar til að uppgötva tengsl á milli eintakabreytileika og sértækrar námsröskunar, án greindarskerðingar, og breytinga í uppbyggingu og virkni heilans, sem áður höfðu verið tengdar við lesskilning og margföldunarskilning. Einnig fundust breytingar í basaröð sem styttir próteinafurð gens og tengjast mjög sterklega við greindarskerðingu og verulegum breytingum í hvíta efni heilans. Niðurstöðurnar sýna að áhrif þessara eintakabreytileika, sem sýna fylgni við taugaþroskaraskanir og geðsjúkdóma, teygjast yfir í aukna áhættu á ADHD og varpa þannig ljósi á fjölbreytt áhrif þessara eintakabreytileika. Niðurstöðurnar benda til þess að taugaþroskaraskanir og geðraskanir séu ekki aðgreindar heldur tengdar raskanir. Dæmin hér að ofan sýna fram á þá kosti sem aðferðir erfðafræðinnar bjóða upp á til þess að aðgreina einkenni og teikn sjúkdóma, sem gerir rannsóknir á tengslum breytinga í heila og vitsmuna mun markvissari

A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo

Funding Information: We thank the participants in this study for their valuable contribution to research. We also thank our colleagues at deCODE who contributed to genotyping and analysis of the WGS data. This research was conducted using the UK Biobank Resource (application number 24898). We acknowledge Stacey Knight, Tyler Barker, Jeffrey L. Anderson, and John F. Carlquist for their contribution to the HerediGene: Population study. We acknowledge the participants and investigators of the FinnGen study. The financial support from the European Commission to the NeuroPain project (FP7#HEALTH-2013-602891-2) and painFACT project (H2020-2020-848099), and the National Institutes of Health (R01DE022905) is acknowledged. Publisher Copyright: © 2021, The Author(s).Vertigo is the leading symptom of vestibular disorders and a major risk factor for falls. In a genome-wide association study of vertigo (Ncases = 48,072, Ncontrols = 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo. Using previous reports of sequence variants associating with age-related hearing impairment and motion sickness, we found eight additional variants that associate with vertigo. Although disorders of the auditory and the vestibular system may co-occur, none of the six genome-wide significant vertigo variants were associated with hearing loss and only one was associated with age-related hearing impairment. Our results uncovered sequence variants associating with vertigo in a genome-wide association study and implicated genes with known roles in inner ear development, maintenance, and disease.Peer reviewe