scholarly journals Genetic associations and architecture of asthma-chronic obstructive pulmonary disease overlap

2020 ◽  
Author(s):  
C. John ◽  
A.L. Guyatt ◽  
N. Shrine ◽  
R. Packer ◽  
T.A. Olafsdottir ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Meta Analysis ◽  
European Ancestry ◽  
Chronic Obstructive ◽  
Genetic Associations ◽  
Obstructive Pulmonary Disease ◽  
Genome Wide ◽  
A Genome ◽  
Stage 1

AbstractSome individuals have characteristics of both asthma and COPD (asthma-COPD overlap, ACO), and evidence suggests they experience worse outcomes than those with either condition alone. Improved knowledge of the genetic architecture would contribute to understanding whether determinants of risk in this group differ from those in COPD or asthma.We conducted a genome-wide association study in 8,068 cases and 40,360 controls of European ancestry from UK Biobank (stage 1). After excluding variants only associated with asthma or COPD we selected 31 variants for further investigation in 12 additional cohorts (stage 2), and discovered eight novel signals for ACO in a meta-analysis of stage 1 and 2 studies.Our signals include an intergenic signal on chromosome 5 not previously associated with asthma, COPD or lung function, and suggest a spectrum of shared and distinct genetic influences in asthma, COPD and ACO. A number of signals may represent loci that predispose to serious long-term consequences in people with asthma.

scholarly journals New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries

2018 ◽  
Author(s):  
Nick Shrine ◽  
Anna L Guyatt ◽  
A Mesut Erzurumluoglu ◽  
Victoria E Jackson ◽  
Brian D Hobbs ◽  
...  
Keyword(s):  
Lung Function ◽  
Drug Targets ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
European Ancestry ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
A Genome ◽  
Disease Associations ◽  
Never Smokers

AbstractReduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, one-half of which are new. In combination these variants strongly predict COPD in deeply-phenotyped patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

scholarly journals A regulatory variant of CHRM3 is associated with cannabis-induced hallucinations in European Americans

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zhongshan Cheng ◽  
Chureerat Phokaew ◽  
Yi-Ling Chou ◽  
Dongbing Lai ◽  
Jacquelyn L. Meyers ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Collaborative Study ◽  
Risk Genes ◽  
European Americans ◽  
Genome Wide ◽  
Nominal Significance ◽  
A Genome ◽  
Regulatory Variant

AbstractCannabis, the most widely used illicit drug, can induce hallucinations. Our understanding of the biology of cannabis-induced hallucinations (Ca-HL) is limited. We used the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) to identify cannabis-induced hallucinations (Ca-HL) among long-term cannabis users (used cannabis ≥1 year and ≥100 times). A genome-wide association study (GWAS) was conducted by analyzing European Americans (EAs) and African Americans (AAs) in Yale-Penn 1 and 2 cohorts individually, then meta-analyzing the two cohorts within population. In the meta-analysis of Yale-Penn EAs (n = 1917), one genome-wide significant (GWS) signal emerged at the CHRM3 locus, represented by rs115455482 (P = 1.66 × 10−10), rs74722579 (P = 2.81 × 10−9), and rs1938228 (P = 1.57 × 10−8); signals were GWS in Yale-Penn 1 EAs (n = 1092) and nominally significant in Yale-Penn 2 EAs (n = 825). Two SNPs, rs115455482 and rs74722579, were available from the Collaborative Study on the Genetics of Alcoholism data (COGA; 3630 long-term cannabis users). The signals did not replicate, but when meta-analyzing Yale-Penn and COGA EAs, the two SNPs’ association signals were increased (meta-P-values 1.32 × 10−10 and 2.60 × 10−9, respectively; n = 4291). There were no significant findings in AAs, but in the AA meta-analysis (n = 3624), nominal significance was seen for rs74722579. The rs115455482*T risk allele was associated with lower CHRM3 expression in the thalamus. CHRM3 was co-expressed with three psychosis risk genes (GABAG2, CHRNA4, and HRH3) in the thalamus and other human brain tissues and mouse GABAergic neurons. This work provides strong evidence for the association of CHRM3 with Ca-HL and provides insight into the potential involvement of thalamus for this trait.

scholarly journals A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Ryoichi Nakamura ◽  
Kazuharu Misawa ◽  
Genki Tohnai ◽  
Masahiro Nakatochi ◽  
Sho Furuhashi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Japanese Population ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
European Ancestry ◽  
Japanese Cohort ◽  
Genome Wide ◽  
Sporadic Als ◽  
A Genome ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

scholarly journals Genome-wide analyses in 1,987,836 participants identify 39 genetic loci associated with sleep apnoea

2020 ◽  
Author(s):  
Adrian I Campos ◽  
Nathan Ingold ◽  
Yunru Huang ◽  
Pik Fang Kho ◽  
Xikun Han ◽  
...  
Keyword(s):  
Complex Traits ◽  
Statistical Power ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Sleep Apnoea ◽  
Risk Scores ◽  
Genetic Associations ◽  
Genome Wide ◽  
A Genome

Rationale: Sleep apnoea is a complex disorder characterised by periods of halted breathing during sleep. Despite its association with serious health conditions such as cardiovascular disease, the aetiology of sleep apnoea remains understudied, and previous genetic studies have failed to identify replicable genetic risk factors. Objective: To advance our understanding of factors that increase susceptibility to sleep apnoea by identifying novel genetic associations. Methods: We conducted a genome-wide association study (GWAS) meta-analysis of sleep apnoea across five cohorts, and a previously published GWAS of apnoea-hypopnea index (N Total =510,484). Further, we used multi-trait analysis of GWAS (MTAG) to boost statistical power, leveraging the high genetic correlations between apnoea, snoring and body mass index. Replication was performed in an independent sample from 23andMe, Inc (N Total =1,477,352; N cases =175,522). Results: Our results revealed 39 independent genomic loci robustly associated with sleep apnoea risk, and significant genetic correlations with multisite chronic pain, sleep disorders, diabetes, high blood pressure, osteoarthritis, asthma and BMI-related traits. We also derived polygenic risk scores for sleep apnoea in a leave-one-out independent cohort and predicted probable sleep apnoea in participants (OR=1.15 to 1.22; variance explained = 0.4 to 0.9%). Conclusions: We report novel genetic markers robustly associated with sleep apnoea risk and substantial molecular overlap with other complex traits, thus advancing our understanding of the underlying biological mechanisms of susceptibility to sleep apnoea.

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

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Astros Th. Skuladottir ◽  
Gyda Bjornsdottir ◽  
Muhammad Sulaman Nawaz ◽  
Hannes Petersen ◽  
Solvi Rognvaldsson ◽  
...  
Keyword(s):  
Association Study ◽  
Hearing Impairment ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Sequence Variants ◽  
Age Related ◽  
Genome Wide ◽  
A Genome

AbstractVertigo 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.

scholarly journals Multi-ancestry meta-analysis of asthma identifies novel associations and highlights the value of increased power and diversity

2021 ◽  
Author(s):  
Kristin Tsuo ◽  
Wei Zhou ◽  
Ying Wang ◽  
Masahiro Kanai ◽  
Shinichi Namba ◽  
...  
Keyword(s):  
Statistical Power ◽  
Complex Disease ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Risk Scores ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Genome Wide ◽  
Order Of Magnitude ◽  
Novel Associations

Asthma is a complex disease that affects millions of people and varies in prevalence by an order of magnitude across geographic regions and populations. However, the extent to which genetic variation contributes to these disparities is unclear, as studies probing the genetics of asthma have been primarily limited to populations of European (EUR) descent. As part of the Global Biobank Meta-analysis Initiative (GBMI), we conducted the largest genome-wide association study of asthma to date (153,763 cases and 1,647,022 controls) via meta-analysis across 18 biobanks spanning multiple countries and ancestries. Altogether, we discovered 180 genome-wide significant loci (p < 5x10-8) associated with asthma, 49 of which are not previously reported. We replicate well-known associations such as IL1RL1 and STAT6, and find that overall the novel associations have smaller effects than previously-discovered loci, highlighting our substantial increase in statistical power. Despite the considerable range in prevalence among biobanks, from 3% to 24%, the genetic effects of associated loci are largely consistent across the biobanks and ancestries. To further investigate the polygenic architecture of asthma, we construct polygenic risk scores (PRS) using a multi-ancestry approach, which yields higher predictive power for asthma in non-EUR populations compared to PRS derived from previous asthma meta-analyses and using other methods. Additionally, we find considerable genetic overlap between asthma and chronic obstructive pulmonary disease (COPD) across ancestries but minimal overlap in enriched biological pathways. Our work underscores the multifactorial nature of asthma development and offers insight into the shared genetic architecture of asthma that may be differentially perturbed by environmental factors and contribute to variation in prevalence.

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