GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis.

Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson's disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis.

Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164 and TCL1A.

Complex effects of sequence variants on lipid levels and coronary artery disease.

Many sequence variants have additive effects on blood lipid levels and, through that, on the risk of coronary artery disease (CAD). We show that variants also have non-additive effects and interact to affect lipid levels as well as affecting variance and correlations. Variance and correlation effects are often signatures of epistasis or gene-environmental interactions. These complex effects can translate into CAD risk. For example, Trp154Ter in FUT2 protects against CAD among subjects with the A1 blood group, whereas it associates with greater risk of CAD in others. His48Arg in ADH1B interacts with alcohol consumption to affect lipid levels and CAD. The effect of variants in TM6SF2 on blood lipids is greatest among those who never eat oily fish but absent from those who often do. This work demonstrates that variants that affect variance of quantitative traits can allow for the discovery of epistasis and interactions of variants with the environment.

Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses.

Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.

Genetic variants associated with syncope implicate neural and autonomic processes.

AIMS: Syncope is a common and clinically challenging condition. In this study, the genetics of syncope were investigated to seek knowledge about its pathophysiology and prognostic implications. METHODS AND RESULTS: This genome-wide association meta-analysis included 56 071 syncope cases and 890 790 controls from deCODE genetics (Iceland), UK Biobank (United Kingdom), and Copenhagen Hospital Biobank Cardiovascular Study/Danish Blood Donor Study (Denmark), with a follow-up assessment of variants in 22 412 cases and 286 003 controls from Intermountain (Utah, USA) and FinnGen (Finland). The study yielded 18 independent syncope variants, 17 of which were novel. One of the variants, p.Ser140Thr in PTPRN2, affected syncope only when maternally inherited. Another variant associated with a vasovagal reaction during blood donation and five others with heart rate and/or blood pressure regulation, with variable directions of effects. None of the 18 associations could be attributed to cardiovascular or other disorders. Annotation with regard to regulatory elements indicated that the syncope variants were preferentially located in neural-specific regulatory regions. Mendelian randomization analysis supported a causal effect of coronary artery disease on syncope. A polygenic score (PGS) for syncope captured genetic correlation with cardiovascular disorders, diabetes, depression, and shortened lifespan. However, a score based solely on the 18 syncope variants performed similarly to the PGS in detecting syncope risk but did not associate with other disorders. CONCLUSION: The results demonstrate that syncope has a distinct genetic architecture that implicates neural regulatory processes and a complex relationship with heart rate and blood pressure regulation. A shared genetic background with poor cardiovascular health was observed, supporting the importance of a thorough assessment of individuals presenting with syncope.

Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement.

OBJECTIVES: Osteoarthritis is a common and severe, multifactorial disease with a well-established genetic component. However, little is known about how genetics affect disease progression, and thereby the need for joint placement. Therefore, we aimed to investigate whether the genetic associations of knee and hip osteoarthritis differ between patients treated with joint replacement and patients without joint replacement. METHODS: We included knee and hip osteoarthritis cases along with healthy controls, altogether counting >700 000 individuals. The cases were divided into two groups based on joint replacement status (surgical vs non-surgical) and included in four genome-wide association meta-analyses: surgical knee osteoarthritis (N = 22 525), non-surgical knee osteoarthritis (N = 38 626), surgical hip osteoarthritis (N = 20 221) and non-surgical hip osteoarthritis (N = 17 847). In addition, we tested for genetic correlation between the osteoarthritis groups and the pain phenotypes intervertebral disc disorder, dorsalgia, fibromyalgia, migraine and joint pain. RESULTS: We identified 52 sequence variants associated with knee osteoarthritis (surgical: 17, non-surgical: 3) or hip osteoarthritis (surgical: 34, non-surgical: 1). For the surgical phenotypes, we identified 10 novel variants, including genes involved in autophagy (rs2447606 in ATG7) and mechanotransduction (rs202127176 in PIEZO1). One variant, rs13107325 in SLC39A8, associated more strongly with non-surgical knee osteoarthritis than surgical knee osteoarthritis. For all other variants, significance and effect sizes were higher for the surgical phenotypes. In contrast, genetic correlations with pain phenotypes tended to be stronger in the non-surgical groups. CONCLUSIONS: Our results indicate differences in genetic associations between knee and hip osteoarthritis depending on joint replacement status.

Thirty novel sequence variants impacting human intracranial volume.

Intracranial volume, measured through magnetic resonance imaging and/or estimated from head circumference, is heritable and correlates with cognitive traits and several neurological disorders. We performed a genome-wide association study meta-analysis of intracranial volume (n = 79 174) and found 64 associating sequence variants explaining 5.0% of its variance. We used coding variation, transcript and protein levels, to uncover 12 genes likely mediating the effect of these variants, including GLI3 and CDK6 that affect cranial synostosis and microcephaly, respectively. Intracranial volume correlates genetically with volumes of cortical and sub-cortical regions, cognition, learning, neonatal and neurological traits. Parkinson's disease cases have greater and attention deficit hyperactivity disorder cases smaller intracranial volume than controls. Our Mendelian randomization studies indicate that intracranial volume associated variants either increase the risk of Parkinson's disease and decrease the risk of attention deficit hyperactivity disorder and neuroticism or correlate closely with a confounder.

Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond.

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.

A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome.

Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10-24, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles.

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology.

Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.

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

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.

Integration of evidence across human and model organism studies: A meeting report.

The National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting's objective was to discuss and evaluate better strategies to integrate genetic, epigenetic, and 'omics data across human and model organisms to achieve deeper mechanistic insight into SUDs. Specific topics were to (a) evaluate the current state of substance use genetics and genomics research and fundamental gaps, (b) identify opportunities and challenges of integration and sharing across species and data types, (c) identify current tools and resources for integration of genetic, epigenetic, and phenotypic data, (d) discuss steps and impediment related to data integration, and (e) outline future steps to support more effective collaboration-particularly between animal model research communities and human genetics and clinical research teams. This review summarizes key facets of this catalytic discussion with a focus on new opportunities and gaps in resources and knowledge on SUDs.

A meta-analysis uncovers the first sequence variant conferring risk of Bell's palsy.

Bell's palsy is the most common cause of unilateral facial paralysis and is defined as an idiopathic and acute inability to control movements of the facial muscles on the affected side. While the pathogenesis remains unknown, previous studies have implicated post-viral inflammation and resulting compression of the facial nerve. Reported heritability estimates of 4-14% suggest a genetic component in the etiology and an autosomal dominant inheritance has been proposed. Here, we report findings from a meta-analysis of genome-wide association studies uncovering the first unequivocal association with Bell's palsy (rs9357446-A; P = 6.79 × 10-23, OR = 1.23; Ncases = 4714, Ncontrols = 1,011,520). The variant also confers risk of intervertebral disc disorders (P = 2.99 × 10-11, OR = 1.04) suggesting a common pathogenesis in part or a true pleiotropy.

A large-scale genome-wide association study meta-analysis of cannabis use disorder.

BACKGROUND: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. METHODS: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. FINDINGS: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. INTERPRETATION: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. FUNDING: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.

Sequence Variants in TAAR5 and Other Loci Affect Human Odor Perception and Naming.

Olfactory receptor (OR) genes in humans form a special class characterized by unusually high DNA sequence diversity, which should give rise to differences in perception and behavior. In the largest genome-wide association study to date based on olfactory testing, we investigated odor perception and naming with smell tasks performed by 9,122 Icelanders, with replication in a separate sample of 2,204 individuals. We discovered an association between a low-frequency missense variant in TAAR5 and reduced intensity rating of fish odor containing trimethylamine (p.Ser95Pro, pcombined = 5.6 × 10-15). We demonstrate that TAAR5 genotype affects aversion to fish odor, reflected by linguistic descriptions of the odor and pleasantness ratings. We also discovered common sequence variants in two canonical olfactory receptor loci that associate with increased intensity and naming of licorice odor (trans-anethole: lead variant p.Lys233Asn in OR6C70, pcombined = 8.8 × 10-16 and pcombined = 1.4 × 10-9) and enhanced naming of cinnamon (trans-cinnamaldehyde; intergenic variant rs317787-T, pcombined = 5.0 × 10-17). Together, our results show that TAAR5 genotype variation influences human odor responses and highlight that sequence diversity in canonical OR genes can lead to enhanced olfactory ability, in contrast to the view that greater tolerance for mutations in the human OR repertoire leads to diminished function.

Common and Rare Sequence Variants Influencing Tumor Biomarkers in Blood.

BACKGROUND: Alpha-fetoprotein (AFP), cancer antigens 15.3, 19.9, and 125, carcinoembryonic antigen, and alkaline phosphatase (ALP) are widely measured in attempts to detect cancer and to monitor treatment response. However, due to lack of sensitivity and specificity, their utility is debated. The serum levels of these markers are affected by a number of nonmalignant factors, including genotype. Thus, it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. METHODS: We performed genome-wide association studies of serum levels of AFP (N = 22,686), carcinoembryonic antigen (N = 22,309), cancer antigens 15.3 (N = 7,107), 19.9 (N = 9,945), and 125 (N = 9,824), and ALP (N = 162,774). We also examined the correlations between levels of these biomarkers and the presence of cancer, using data from a nationwide cancer registry. RESULTS: We report a total of 84 associations of 79 sequence variants with levels of the six biomarkers, explaining between 2.3% and 42.3% of the phenotypic variance. Among the 79 variants, 22 are cis (in- or near the gene encoding the biomarker), 18 have minor allele frequency less than 1%, 31 are coding variants, and 7 are associated with gene expression in whole blood. We also find multiple conditions associated with higher biomarker levels. CONCLUSIONS: Our results provide insights into the genetic contribution to diversity in concentration of tumor biomarkers in blood. IMPACT: Genetic correction of biomarker values could improve prediction algorithms and decision-making based on these biomarkers.

Genome-wide association study implicates CHRNA2 in cannabis use disorder.

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.

A PRPH splice-donor variant associates with reduced sural nerve amplitude and risk of peripheral neuropathy.

Nerve conduction (NC) studies generate measures of peripheral nerve function that can reveal underlying pathology due to axonal loss, demyelination or both. We perform a genome-wide association study of sural NC amplitude and velocity in 7045 Icelanders and find a low-frequency splice-donor variant in PRPH (c.996+1G>A; MAF = 1.32%) associating with decreased NC amplitude but not velocity. PRPH encodes peripherin, an intermediate filament (IF) protein involved in cytoskeletal development and maintenance of neurons. Through RNA and protein studies, we show that the variant leads to loss-of-function (LoF), as when over-expressed in a cell line devoid of other IFs, it does not allow formation of the normal filamentous structure of peripherin, yielding instead punctate protein inclusions. Recall of carriers for neurological assessment confirms that from an early age, homozygotes have significantly lower sural NC amplitude than non-carriers and are at risk of a mild, early-onset, sensory-negative, axonal polyneuropathy.