Phenotypic and Genotypic Associations Between Migraine and Lipoprotein Subtractions

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012919
Author(s):  
Yanjun Guo ◽  
Iyas Daghlas ◽  
Padhraig Gormley ◽  
Franco Giulianini ◽  
Paul M Ridker ◽  
...  
Keyword(s):  
Genetic Correlation ◽  
Genetic Relationships ◽  
Meta Analysis ◽  
European Ancestry ◽  
Health Study ◽  
Lipoprotein Subfractions ◽  
Genetic Components ◽  
The Uk ◽  
Summary Data

Background and Objective:To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions.Methods:We evaluated phenotypic associations between migraine and 19 lipoprotein subfractions measures in the Women’s Genome Health Study (WGHS, N=22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium (IHGC) for migraine (Ncase=54,552, Ncontrol=297,970) and combined summary data for lipoprotein subfractions (N up to 47,713).Results:There was a significant phenotypic association (odds ratio=1.27 [95% confidence interval:1.12-1.44]) and a significant genetic correlation at 0.18 (P=0.001) between migraine and triglyceride-rich lipoproteins (TRLP) concentration but not for LDL or HDL subfractions. Mendelian randomization (MR) estimates were largely null implying that pleiotropy rather than causality underlies the genetic correlation between migraine and lipoprotein subfractions. Pleiotropy was further supported in cross-trait meta-analysis revealing significant shared signals at four loci (chr2p21 harboring THADA, chr5q13.3 harboring HMGCR, chr6q22.31 harboring HEY2, and chr7q11.23 harboring MLXIPL) between migraine and lipoprotein subfractions. Three of these loci were replicated for migraine (P<0.05) in a smaller sample from the UK Biobank. The shared signal at chr5q13.3 colocalized with expression of HMGCR, ANKDD1B, and COL4A3BP in multiple tissues.Conclusions:The current study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may be help identify potential targets for future migraine therapeutics.Classification of Evidence:This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions.

Abstract P147: Genome Wide Assessment of Shared Genetic Architecture Between Rheumatoid Arthritis and Cardiovascular Diseases Using the UK Biobank Data

Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Yanjun Guo ◽  
Wonil Chung ◽  
Zhilei Shan ◽  
Liming Liang
Keyword(s):  
Cardiovascular Diseases ◽  
Genetic Correlation ◽  
Multiple Testing ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Uk Biobank ◽  
Increased Risk ◽  
The Uk ◽  
Cardiovascular Traits ◽  
Shared Genetic

Background: Patients with RA have a 2-10 folds increased risk of cardiovascular diseases (CVD) and CVD accounts for almost 50% of the excess mortality in patients with RA when compared with general population, but the mechanisms underlying such associations are largely unknown. Methods: We examined the genetic correlation, causality, and shared genetic variants between RA (Ncase=6,756, Ncontrol=452,476) and CVD (Ncase=44,246, Ncontrol=414,986) using LD Score regression (LDSC), generalized summary-data-based Mendelian Randomization (GSMR), and cross-trait meta-analysis in the UK Biobank Data. Results: In the present study, RA was significantly genetically correlated with MI, angina, CHD, and CVD after correcting for multiple testing (Rg ranges from 0.40 to 0.43, P<0.05/5). Interestingly, when stratified by frequent usage of aspirin and paracetamol, we observed increased genetic correlation between RA and CVD for participants without aspirin usage ( Rg increased to 0.54 [95%CI: 0.54, 0.78] for angina; P value=6.69х10 -6 ), and for participants with usage of paracetamol ( Rg increased to 0.75 [95%CI: 0.20, 1.29] for MI; P value=8.90х10 -3 ). Cross-trait meta-analysis identified 9 independent loci that were shared between RA and at least one of the genetically correlated CVD traits including PTPN22 at chr1p13.2 , BCL2L11 at chr2q13 , and CCR3 at chr3p21.31 ( P single trait <1х10 -3 and P meta <5х10 -8 ) highlighting potential shared etiology between them which include accelerating atherosclerosis and upregulating oxidative stress and vascular permeability. Finally, Mendelian randomization analyses observed inconsistent instrumental effects and were unable to conclude the causality and directionality between RA and CVD. Conclusion: Our results supported positive genetic correlation between RA and multiple cardiovascular traits, and frequent usage of aspirin and paracetamol may modify their associations, but instrumental analyses were unable to conclude the causality and directionality between them.

scholarly journals Genetically regulated gene expression underlies lipid traits in Hispanic cohorts

2018 ◽  
Author(s):  
Angela Andaleon ◽  
Lauren S. Mogil ◽  
Heather E. Wheeler
Keyword(s):  
Association Studies ◽  
Lipid Level ◽  
Meta Analysis ◽  
Plasma Lipid ◽  
European Ancestry ◽  
Health Study ◽  
Lipid Levels ◽  
Multiple Phenotypes ◽  
Significant Gene ◽  
Regulated Gene Expression

AbstractPlasma lipid levels are risk factors for cardiovascular disease, a leading cause of death worldwide. While many studies have been conducted in genetic variation underlying lipid levels, they mainly comprise individuals of European ancestry and thus their transferability to non-European populations is unclear. We performed genome-wide (GWAS) and imputed transcriptome-wide association studies of four lipid traits in the Hispanic Community Health Study/Study of Latinos cohort (HCHS/SoL, n = 11,103), replicated top hits in the Multi-Ethnic Study of Atherosclerosis (MESA, n = 3,855), and compared the results to the larger, predominantly European ancestry meta-analysis by the Global Lipids Genetics Consortium (GLGC, n = 196,475). In our GWAS, we found significant SNP associations in regions within or near known lipid genes, but in our admixture mapping analysis, we did not find significant associations between local ancestry and lipid phenotypes. In the imputed transcriptome-wide association study in multiple tissues and in different ethnicities, we found 59 significant gene-tissue-phenotype associations (P < 3.61×10−8) with 14 unique significant genes, many of which occurred across multiple phenotypes, tissues, and ethnicities and replicated in MESA (45/59) and in GLGC (44/59). These include well-studied lipid genes such as SORT1, CETP, and PSRC1, as well as genes that have been implicated in cardiovascular phenotypes, such as CCL22 and ICAM1. The majority (40/59) of significant associations colocalized with expression quantitative trait loci (eQTLs), indicating a possible mechanism of gene regulation in lipid level variation. To fully characterize the genetic architecture of lipid traits in diverse populations, larger studies in non-European ancestry populations are needed.

scholarly journals Meta-analysis of problematic alcohol use in 435,563 individuals identifies 29 risk variants and yields insights into biology, pleiotropy and causality

2019 ◽  
Author(s):  
Hang Zhou ◽  
Julia M. Sealock ◽  
Sandra Sanchez-Roige ◽  
Toni-Kim Clarke ◽  
Daniel Levey ◽  
...  
Keyword(s):  
Substance Use ◽  
Alcohol Use ◽  
Genetic Relationships ◽  
Meta Analysis ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Problematic Alcohol ◽  
Risk Variants ◽  
Problematic Alcohol Use

AbstractProblematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies (GWASs) have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU combining alcohol use disorder and problematic drinking in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n=67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in genomic conserved and regulatory regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior, and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other outcomes.

Shared genetic influences on depression and menopause symptoms

2021 ◽  
pp. 1-11
Author(s):  
Joeri J. Meijsen ◽  
Hanyang Shen ◽  
Mytilee Vemuri ◽  
Natalie L. Rasgon ◽  
Karestan C. Koenen ◽  
...  
Keyword(s):  
Genetic Correlation ◽  
Hot Flashes ◽  
Medication Use ◽  
European Ancestry ◽  
Genetic Influences ◽  
Uk Biobank ◽  
Genetic Analyses ◽  
Correlation Analyses ◽  
The Uk ◽  
Shared Genetic

Abstract Background Women experience major depression and post-traumatic stress disorder (PTSD) approximately twice as often as men. Estrogen is thought to contribute to sex differences in these disorders, and reduced estrogen is also known to be a key driver of menopause symptoms such as hot flashes. Moreover, estrogen is used to treat menopause symptoms. In order to test for potential shared genetic influences between menopause symptoms and psychiatric disorders, we conducted a genome-wide association study (GWAS) of estrogen medication use (as a proxy for menopause symptoms) in the UK Biobank. Methods The analysis included 232 993 women aged 39–71 in the UK Biobank. The outcome variable for genetic analyses was estrogen medication use, excluding women using hormonal contraceptives. Trans-ancestry GWAS meta-analyses were conducted along with genetic correlation analyses on the European ancestry GWAS results. Hormone usage was also tested for association with depression and PTSD. Results GWAS of estrogen medication use (compared to non-use) identified a locus in the TACR3 gene, which was previously linked to hot flashes in menopause [top rs77322567, odds ratio (OR) = 0.78, p = 7.7 × 10−15]. Genetic correlation analyses revealed shared genetic influences on menopause symptoms and depression (rg = 0.231, s.e.= 0.055, p = 2.8 × 10−5). Non-genetic analyses revealed higher psychiatric symptoms scores among women using estrogen medications. Conclusions These results suggest that menopause symptoms have a complex genetic etiology which is partially shared with genetic influences on depression. Moreover, the TACR3 gene identified here has direct clinical relevance; antagonists for the neurokinin 3 receptor (coded for by TACR3) are effective treatments for hot flashes.

scholarly journals Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study

2018 ◽  
Vol 64 (1) ◽  
pp. 231-241 ◽  
Author(s):  
Shafqat Ahmad ◽  
Samia Mora ◽  
Paul W Franks ◽  
Marju Orho-Melander ◽  
Paul M Ridker ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Genetic Risk Score ◽  
Normal Weight ◽  
Differential Association ◽  
European Ancestry ◽  
Health Study ◽  
Resonance Spectroscopy ◽  
Lipoprotein Subfractions ◽  
Total N ◽  
Weighted Genetic Risk Score

Abstract BACKGROUND Previous results from Scandinavian cohorts have shown that obesity accentuates the effects of common genetic susceptibility variants on increased triglycerides (TG). Whether such interactions are present in the US population and further selective for particular TG-rich lipoprotein subfractions is unknown. METHODS We examined these questions using body mass index (BMI) and waist circumference (WC) among women of European ancestry from the Women's Genome Health Study (WGHS) (n = 21840 for BMI; n = 19313 for WC). A weighted genetic risk score (TG-wGRS) based on 40 published TG-associated single-nucleotide polymorphisms was calculated using published effect estimates. RESULTS Comparing overweight (BMI ≥ 25 kg/m2) and normal weight (BMI &lt; 25 kg/m2) WGHS women, each unit increase of TG-wGRS was associated with TG increases of 1.013% and 1.011%, respectively, and this differential association was significant (Pinteraction = 0.014). Metaanalyses combining results for WGHS BMI with the 4 Scandinavian cohorts (INTER99, HEALTH2006, GLACIER, MDC) (total n = 40026) yielded a more significant interaction (Pinteraction = 0.001). Similarly, we observed differential association of the TG-wGRS with TG (Pinteraction = 0.006) in strata of WC (&lt;80 cm vs ≥80 cm). Metaanalysis with 2 additional cohorts reporting WC (INTER99 and HEALTH2006) (total n = 27834) was significant with consistent effects (Pinteraction = 0.006). We also observed highly significant interactions of the TG-wGRS across the strata of BMI with very large, medium, and small TG-rich lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy (all Pinteractions &lt; 0.0001). The differential effects were strongest for very large TG-rich lipoprotein. CONCLUSIONS Our results support the original findings and suggest that obese individuals may be more susceptible to aggregated genetic risk associated with common TG-raising alleles, with effects accentuated in the large TG-rich lipoprotein subfraction.

scholarly journals Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323868
Author(s):  
Tenghao Zheng ◽  
David Ellinghaus ◽  
Simonas Juzenas ◽  
François Cossais ◽  
Greta Burmeister ◽  
...  
Keyword(s):  
Genetic Correlation ◽  
Genome Wide Association Study ◽  
Age Of Onset ◽  
Meta Analysis ◽  
Smooth Muscles ◽  
European Ancestry ◽  
Risk Scores ◽  
Haemorrhoidal Disease ◽  
Genome Wide ◽  
Endothelial Development

ObjectiveHaemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.DesignWe conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.ResultsWe demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.ConclusionHEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

scholarly journals Comprehensive genetic analysis of the human lipidome identifies novel loci controlling lipid homeostasis with links to coronary artery disease

2021 ◽  
Author(s):  
Gemma Cadby ◽  
Corey Giles ◽  
Phillip E Melton ◽  
Kevin Huynh ◽  
Natalie A Mellett ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Lipid Metabolism ◽  
Coronary Artery ◽  
Meta Analysis ◽  
Lipid Homeostasis ◽  
Health Study ◽  
Mechanistic Pathway ◽  
Lipid Species ◽  
Artery Disease ◽  
The Uk

We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species that are putatively in the mechanistic pathway to coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 phenotyped individuals from the Busselton Health Study. In our discovery GWAS we identified 667 independent loci associations with these lipid species (479 novel), followed by meta-analysis and validation in two independent cohorts. Lipid endophenotypes (134) identified for CAD were associated with variation at 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ~456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P<1x10-3), 43 loci were associated with at least one of the 134 lipid endophenotypes. The findings of this study illustrate the value of integrative biology to investigate the genetics and lipid metabolism in the aetiology of atherosclerosis and CAD, with implications for other complex diseases.

scholarly journals A novel method for an unbiased estimate of cross-ancestry genetic correlation using individual-level data

2021 ◽  
Author(s):  
Md. Moksedul Momin ◽  
Jisu Shin ◽  
Soohyun Lee ◽  
Buu Truong ◽  
Beben Benyamin ◽  
...  
Keyword(s):  
Genetic Correlation ◽  
Complex Trait ◽  
European Ancestry ◽  
Genomic Relationship Matrix ◽  
Relationship Matrix ◽  
Individual Level ◽  
Level Data ◽  
Specific Allele ◽  
Novel Method ◽  
The Uk

AbstractCross-ancestry genetic correlation is an important parameter to understand the genetic relationship between two ancestry groups for a complex trait. However, existing methods cannot properly account for ancestry-specific genetic architecture, which is diverse across ancestries, producing biased estimates of cross-ancestry genetic correlation. Here, we present a method to construct a genomic relationship matrix (GRM) that can correctly account for the relationship between ancestry-specific allele frequencies and ancestry-specific causal effects. Through comprehensive simulations, we show that the proposed method outperforms existing methods in the estimations of SNP-based heritability and cross-ancestry genetic correlation. The proposed method is further applied to six anthropometric traits from the UK Biobank data across 5 ancestry groups. One of our findings is that for obesity, the estimated genetic correlation between African and European ancestry cohorts is significantly different from unity, suggesting that obesity is genetically heterogenous between these two ancestry groups.

scholarly journals Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis

2018 ◽  
Author(s):  
Sarah E. Graham ◽  
Jonas B. Nielsen ◽  
Matthew Zawistowski ◽  
Wei Zhou ◽  
Lars G. Fritsche ◽  
...  
Keyword(s):  
Kidney Function ◽  
Kidney Development ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Risk Scores ◽  
Health Study ◽  
Genetic Components ◽  
Gene Sets ◽  
Meta Analyses ◽  
Stratified Analysis

AbstractChronic Kidney Disease (CKD) is a growing health burden currently affecting 10-15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. Previous genome-wide association study (GWAS) meta-analyses of CKD and eGFR or related phenotypes have identified a number of variants associated with kidney function, but these only explain a fraction of the variability in kidney phenotypes attributed to genetic components. To extend these studies, we analyzed data from the Nord-Trøndelag Health Study (HUNT), which is more densely imputed than previous studies, and performed a GWAS meta-analysis of eGFR with publicly available summary statistics, more than doubling the sample size of previous meta-analyses. We identified 147 loci (53 novel loci) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Moreover, genes at these loci show enriched expression in urogenital tissues and highlight gene sets known to play a role in kidney function. In addition, sex-stratified analysis identified three regions (prioritized genes: PPM1J, MCL1, and SLC47A1) with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD but improve detection only modestly compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD.

scholarly journals GENE-11. LDSCORE REGRESSION IDENTIFIES NOVEL ASSOCIATIONS BETWEEN GLIOMA AND AUTO-IMMUNE CONDITIONS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi99-vi100
Author(s):  
Quinn Ostrom ◽  
Jacob Edelson ◽  
Jinyoung Byun ◽  
Younghun Han ◽  
Kyle Walsh ◽  
...  
Keyword(s):  
Allergic Rhinitis ◽  
Genetic Correlation ◽  
Meta Analysis ◽  
Epidemiological Studies ◽  
Summary Statistics ◽  
Case Control Studies ◽  
Risk Variants ◽  
History Of ◽  
The Uk ◽  
Novel Associations

Abstract BACKGROUND Prior epidemiological studies in glioma have identified 25 germline risk variants, as well as risk associations with exposure to ionizing radiation (which increases risk) and history of allergies and aspirin use (which decrease risk). In this analysis we LDscore regression, which leverages single SNP associations and known patterns of linkage disequilibrium (LD) to estimate the genetic correlation between phenotypes, to confirm prior associations as well as attempt to identify novel phenotype associations for traits not previously assessed that may improve genetic prediction for glioma. METHODS Summary statistics for all glioma, GBM, and non-GBM were obtained from a prior meta-analysis conducted by Melin, et al. Summary statistics for 13 immune- and atopy-related traits were obtained from the prior case-control studies and the UK biobank. Data were filtered to include only SNPs with imputation INFO value >0.7, and minor allele frequency >0.01, excluding SNPs within the HLA region. Pairwise genetic correlation between these traits was generated using LDSC. Associations were considered significant at p< 0.05 RESULTS Significant negative correlations were identified between glioma and ulcerative colitis (rg= -0.4039, p=4.91x10-10), celiac disease (rg= -0.2028, p=1.18x10-4), lupus (rg= -0.0956, p=0.0083), and multiple sclerosis (rg= -0.5755, p=4.46x10-9). These associations were generally consistent in both GBM and non-GBM. There was a significant correlation between both self-reported (rg= -0.102, p=0.0233) and doctor diagnosed (rg= -0.116, p=0.0305) hayfever/allergic rhinitis and GBM only. CONCLUSIONS This analysis demonstrates a genetic basis for previously identified protective effect of allergic rhinitis on GBM, and identifies novel associations between multiple auto-immune traits and glioma. Further studies are necessary in order to confirm these associations and identify the mechanism through which increased immune activity may lower risk of glioma.

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