scholarly journals New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hélène Choquet ◽  
Jie Yin ◽  
Alice S. Jacobson ◽  
Brandon H. Horton ◽  
Thomas J. Hoffmann ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Meta Analysis ◽  
Primary Headache ◽  
Headache Disorder ◽  
European Ancestry ◽  
Summary Statistics ◽  
Uk Biobank ◽  
Susceptibility Loci ◽  
Primary Headache Disorder ◽  
Genome Wide

AbstractMigraine is a common disabling primary headache disorder that is ranked as the most common neurological cause of disability worldwide. Women present with migraine much more frequently than men, but the reasons for this difference are unknown. Migraine heritability is estimated to up to 57%, yet much of the genetic risk remains unaccounted for, especially in non-European ancestry populations. To elucidate the etiology of this common disorder, we conduct a multiethnic genome-wide association meta-analysis of migraine, combining results from the GERA and UK Biobank cohorts, followed by a European-ancestry meta-analysis using public summary statistics. We report 79 loci associated with migraine, of which 45 were novel. Sex-stratified analyses identify three additional novel loci (CPS1, PBRM1, and SLC25A21) specific to women. This large multiethnic migraine study provides important information that may substantially improve our understanding of the etiology of migraine susceptibility.

scholarly journals Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

2021 ◽  
Vol 53 (1) ◽  
pp. 65-75
Author(s):  
David V. Conti ◽  
Burcu F. Darst ◽  
Lilit C. Moss ◽  
Edward J. Saunders ◽  
Xin Sheng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Prediction ◽  
Genetic Risk ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Susceptibility Loci ◽  
Genetic Risk Prediction ◽  
Genome Wide

scholarly journals Associations of Lipid-related SNPs with Circulating Phylloquinone Are Proportional with Triglycerides (P15-008-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jennifer Kelly ◽  
Hassan Dashti ◽  
Jose M Ordovas ◽  
Gregory Matuszek ◽  
Caren Smith ◽  
...  
Keyword(s):  
Goodness Of Fit ◽  
Agricultural Research ◽  
Meta Analysis ◽  
Genetic Risk Score ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Summary Statistics ◽  
Linear Association ◽  
Genome Wide ◽  
A Genome

Abstract Objectives Phylloquinone is transported on triglyceride-rich lipoproteins. Preliminary evidence from a genome-wide association meta-analysis suggests that genetic variants that influence triglycerides (TGs), such as rs964184 at the APOA1/C3/A4/A5 gene cluster, also influence circulating phylloquinone. To further evaluate this overlap, we examined the linear relationship between a weighted TG genetic risk score (wTG-GRS) with circulating phylloquinone. Methods We constructed a wTG-GRS comprised of 20 SNPs that were previously associated with TGs in a genome-wide association meta-analysis for blood lipids (n > 188,000 individuals of European ancestry). The assigned weights corresponded to the effect-sizes (β) reported for each SNP's association with TGs. With meta-analytic summary statistic data from a separate genome-wide association meta-analysis of circulating phylloquinone (n = 2138 individuals of European ancestry), a statistical technique was used to approximate the linear association of the wTG-GRS with circulating phylloquinone. A p-value of 0.05 for the estimate was considered statistically significant. First, the estimate was calculated without adjustment for TGs using Model 1 summary statistics, then calculated with adjustment for TGs using Model 2 summary statistics. Results The estimate for the linear association of the wTG-GRS with circulating phylloquinone was significant without and with adjustment for TGs (Model 1: β = 0.052, P = < 0.0001, Model 2: β = 0.027, P = 0.0001, respectively). The goodness-of-fit of the model was improved from Model 1 (p-het = 0.022) to Model 2 (p-het = 0.054). Conclusions The associations of TG-related SNPs with circulating phylloquinone were proportional to their associations with TGs. This provides further evidence of the shared genetic links between TGs and phylloquinone and suggests genetic studies of vitamin K should consider TGs. Funding Sources Study supported by the USDA Agricultural Research Service under Cooperative Agreement No. 58-1950-7-707 and NHLBI T32HL069772.

scholarly journals Perceived triggers of primary headache disorders: A meta-analysis

Cephalalgia ◽  
2017 ◽  
Vol 38 (6) ◽  
pp. 1188-1198 ◽  
Author(s):  
A Brooke Walters Pellegrino ◽  
Rachel E Davis-Martin ◽  
Timothy T Houle ◽  
Dana P Turner ◽  
Todd A Smitherman
Keyword(s):  
Meta Analysis ◽  
Experimental Studies ◽  
Primary Headache ◽  
Headache Disorder ◽  
Assessment Method ◽  
Tension Type Headache ◽  
Headache Disorders ◽  
Primary Headache Disorder ◽  
Primary Headache Disorders ◽  
Analytic Review

Objective To quantitatively synthesize extant literature on perceived triggers of primary headache disorders. Methods A meta-analytic review of headache trigger survey studies was conducted. Endorsement rates, assessment method, and headache and sample characteristics were extracted from included articles. Separate random-effects models were used to assess trigger endorsement rates and post-hoc meta-regressions examined potential moderator variables. Results 85 articles from 1958 to 2015 were included, involving 27,122 participants and querying 420 unique triggers (collapsed into 15 categories). Four-fifths (0.81; 95% CI .75 to .86) of individuals with migraine or tension-type headache endorsed at least one trigger. Rates increased with the number of categories queried (OR: 1.18, 1.08–1.30) and year of publication (OR: 1.04, 1.00–1.08). The triggers most commonly endorsed were stress (.58, .53–.63) and sleep (.41, .36–.47). Conclusions Extreme heterogeneity characterizes the headache trigger literature. Most individuals with a primary headache disorder perceive their attacks to be triggered by one or more precipitants, the most common of which are stress and sleep. However, trigger endorsement is influenced by method of assessment. Enhancing methodological consistency and prioritizing experimental studies would improve our understanding of headache triggers.

scholarly journals Multi-Ancestry Meta-Analysis yields novel genetic discoveries and ancestry-specific associations

2021 ◽  
Author(s):  
Patrick Turley ◽  
Alicia R. Martin ◽  
Grant Goldman ◽  
Hui Li ◽  
Masahiro Kanai ◽  
...  
Keyword(s):  
Error Rate ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
East Asian ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Summary Statistics ◽  
Type 1 Error ◽  
Genome Wide

ABSTRACTWe present a new method, Multi-Ancestry Meta-Analysis (MAMA), which combines genome-wide association study (GWAS) summary statistics from multiple populations to produce new summary statistics for each population, identifying novel loci that would not have been discovered in either set of GWAS summary statistics alone. In simulations, MAMA increases power with less bias and generally lower type-1 error rate than other multi-ancestry meta-analysis approaches. We apply MAMA to 23 phenotypes in East-Asian- and European-ancestry populations and find substantial gains in power. In an independent sample, novel genetic discoveries from MAMA replicate strongly.

scholarly journals Genome-wide association study followed by trans-ancestry meta-analysis identify 17 new risk loci for schizophrenia

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jiewei Liu ◽  
Shiwu Li ◽  
Xiaoyan Li ◽  
Wenqiang Li ◽  
Yongfeng Yang ◽  
...  
Keyword(s):  
Association Study ◽  
Chinese Population ◽  
Meta Analysis ◽  
Han Chinese ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Summary Statistics ◽  
Han Chinese Population ◽  
Genome Wide

Abstract Background Over 200 schizophrenia risk loci have been identified by genome-wide association studies (GWASs). However, the majority of risk loci were identified in populations of European ancestry (EUR), potentially missing important biological insights. It is important to perform 5 GWASs in non-European populations. Methods To identify novel schizophrenia risk loci, we conducted a GWAS in Han Chinese population (3493 cases and 4709 controls). We then performed a large-scale meta-analysis (a total of 143,438 subjects) through combining our results with previous GWASs conducted in EAS and EUR. In addition, we also carried out comprehensive post-GWAS analysis, including heritability partitioning, enrichment of schizophrenia associations in tissues and cell types, trancscriptome-wide association study (TWAS), expression quantitative trait loci (eQTL) and differential expression analysis. Results We identified two new schizophrenia risk loci, including associations in SHISA9 (rs7192086, P = 4.92 × 10-08) and PES1 (rs57016637, P = 2.33 × 10−11) in Han Chinese population. A fixed-effect meta-analysis (a total of 143,438 subjects) with summary statistics from EAS and EUR identifies 15 novel genome-wide significant risk loci. Heritability partitioning with linkage disequilibrium score regression (LDSC) reveals a significant enrichment of schizophrenia heritability in conserved genomic regions, promoters, and enhancers. Tissue and cell-type enrichment analyses show that schizophrenia associations are significantly enriched in human brain tissues and several types of neurons, including cerebellum neurons, telencephalon inhibitory, and excitatory neurons. Polygenic risk score profiling reveals that GWAS summary statistics from trans-ancestry meta-analysis (EAS + EUR) improves prediction performance in predicting the case/control status of our sample. Finally, transcriptome-wide association study (TWAS) identifies risk genes whose cis-regulated expression change may have a role in schizophrenia. Conclusions Our study identifies 17 novel schizophrenia risk loci and highlights the importance and necessity of conducting genetic study in different populations. These findings not only provide new insights into genetic etiology of schizophrenia, but also facilitate to delineate the pathophysiology of schizophrenia and develop new therapeutic targets.

scholarly journals Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers

PLoS Genetics ◽  
2021 ◽  
Vol 17 (3) ◽  
pp. e1009254
Author(s):  
Corina Lesseur ◽  
Aida Ferreiro-Iglesias ◽  
James D. McKay ◽  
Yohan Bossé ◽  
Mattias Johansson ◽  
...  
Keyword(s):  
Squamous Cell ◽  
Meta Analysis ◽  
Squamous Cell Carcinomas ◽  
European Ancestry ◽  
Susceptibility Loci ◽  
Gene Set Enrichment ◽  
Risk Variants ◽  
Genome Wide ◽  
Genome Wide Search ◽  
Shared Genetic

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.

scholarly journals A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Nada A. Al-Tassan ◽  
Nicola Whiffin ◽  
Fay J. Hosking ◽  
Claire Palles ◽  
Susan M. Farrington ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Association Studies ◽  
Meta Analysis ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Risk Variants ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Long Non Coding Rna

Abstract Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10−8, odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10−8; OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10-8; OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.

scholarly journals Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy

2020 ◽  
Vol 31 (12) ◽  
pp. 2949-2963
Author(s):  
Ming Li ◽  
Ling Wang ◽  
Dian-Chun Shi ◽  
Jia-Nee Foo ◽  
Zhong Zhong ◽  
...  
Keyword(s):  
Genetic Heterogeneity ◽  
Meta Analysis ◽  
High Linkage Disequilibrium ◽  
European Ancestry ◽  
Significant Heterogeneity ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
Chinese Descent ◽  
Risk Snps ◽  
Two Populations

BackgroundEighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk.MethodsGenome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny.ResultsIdentification of three novel loci (rs6427389 on 1q23.1 [P=8.18×10−9, OR=1.132], rs6942325 on 6p25.3 [P=1.62×10−11, OR=1.165], and rs2240335 on 1p36.13 [P=5.10×10−9, OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119).ConclusionsA meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs.  These variants may explain susceptibility differences between Chinese and European populations.

scholarly journals Twenty-Five Novel Loci for Carotid Intima-Media Thickness: A Genome-Wide Association Study in >45 000 Individuals and Meta-Analysis of >100 000 Individuals

2021 ◽  
Author(s):  
Ming Wai Yeung ◽  
Siqi Wang ◽  
Yordi J. van de Vegte ◽  
Oleg Borisov ◽  
Jessica van Setten ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Intima Media Thickness ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Susceptibility Loci ◽  
Media Thickness ◽  
Genome Wide ◽  
A Genome ◽  
Artery Disease

Objective: Carotid artery intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. Twenty susceptibility loci for cIMT were previously identified and the identification of additional susceptibility loci furthers our knowledge on the genetic architecture underlying atherosclerosis. Approach and Results: We performed 3 genome-wide association studies in 45 185 participants from the UK Biobank study who underwent cIMT measurements and had data on minimum, mean, and maximum thickness. We replicated 15 known loci and identified 20 novel loci associated with cIMT at P <5×10 −8 . Seven novel loci ( ZNF385D , AD AMTS9 , EDNRA , HAND2 , MYOCD , ITCH/EDEM2/ matrix metalloproteinase [ MMP ] 24 , and MRTFA ) were identified in all 3 phenotypes. An additional new locus ( LOXL1 ) was identified in the meta-analysis of the 3 phenotypes. Sex interaction analysis revealed sex differences in 7 loci including a novel locus ( SYNE3 ) in males. Meta-analysis of UK Biobank data with a previous meta-analysis led to identification of three novel loci ( APOB, FIP1L1, and LOXL4 ). Transcriptome-wide association analyses implicated additional genes ARHGAP42 , NDRG4 , and KANK2 . Gene set analysis showed an enrichment in extracellular organization and the PDGF (platelet-derived growth factor) signaling pathway. We found positive genetic correlations of cIMT with coronary artery disease r g =0.21 ( P =1.4×10 -7 ), peripheral artery disease r g =0.45 ( P =5.3×10 -5 ), and systolic blood pressure r g =0.30 ( P =4.0×10 -18 ). A negative genetic correlation between average of maximum cIMT and high-density lipoprotein was found r g =−0.12 ( P =7.0×10 -4 ). Conclusions: Genome-wide association meta-analyses in >100 000 individuals identified 25 novel loci associated with cIMT providing insights into genes and tissue-specific regulatory mechanisms of proatherosclerotic processes. We found evidence for shared biological mechanisms with cardiovascular diseases.

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