Participants Of European Ancestry Research Articles

Markers of kidney function, genetic variation related to cognitive function, and cognitive performance in the UK Biobank

BackgroundChronic kidney disease has been linked to worse cognition. However, this association may be dependent on the marker of kidney function used, and studies assessing modification by genetics are lacking. This study examined associations between multiple measures of kidney function and assessed effect modification by a polygenic score for general cognitive function.MethodsIn this cross-sectional study of up to 341,208 European ancestry participants from the UK Biobank study, we examined associations between albuminuria and estimated glomerular filtration rate based on creatinine (eGFRcre) or cystatin C (eGFRcys) with cognitive performance on tests of verbal-numeric reasoning, reaction time and visual memory. Adjustment for confounding factors was performed using multivariate regression and propensity-score matching. Interaction between kidney function markers and a polygenic risk score for general cognitive function was also assessed.ResultsAlbuminuria was associated with worse performance on tasks of verbal-numeric reasoning (β(points) = -0.09, p < 0.001), reaction time (β(milliseconds) = 7.06, p < 0.001) and visual memory (β(log errors) = 0.013, p = 0.01). A polygenic score for cognitive function modified the association between albuminuria and verbal-numeric reasoning with significantly lower scores in those with albuminuria and a lower polygenic score (p = 0.009). Compared to participants with eGFRcre ≥ 60 ml/min, those with eGFRcre < 60 ml/min had lower verbal-numeric reasoning scores and slower mean reaction times (verbal numeric reasoning β = -0.11, p < 0.001 and reaction time β = 6.08, p < 0.001 for eGFRcre < 60 vs eGFRcre ≥ 60). Associations were stronger using cystatin C-based eGFR than creatinine-based eGFR (verbal numeric reasoning β = -0.21, p < 0.001 and reaction time β = 11.21, p < 0.001 for eGFRcys < 60 vs eGFRcys ≥ 60).ConclusionsIncreased urine albumin is associated with worse cognition, but this may depend on genetic risk. Cystatin C-based eGFR may better predict cognitive performance than creatinine-based estimates.

Causal Association Between Tea Consumption and Bone Health: A Mendelian Randomization Study.

BackgroundMuch observational research reported that tea consumption decreases the risk of osteoarthritis (OA), rheumatoid arthritis (RA), and osteoporosis (OP) which are the three major bone disorders. However, the observed correlation is inconclusive. To determine the causal relationship between genetically predicted tea intake and OA, RA, and OP, we performed a two-sample Mendelian randomization (MR) study based on large samples.MethodsThe European population’s genome-wide association meta-analysis (GWAS) dataset identified SNPs associated with tea consumption was obtained from Neale Lab’s analysis of UK Biobank data that comprised 349,376 participants of European ancestry. We extracted genetic data for knee OA (17,885 controls and 4,462 cases), hip OA (50,898 controls and 12,625 cases), and RA (43,923 controls and 14,361 cases) from the UK Biobank and OP cases (93083 controls and 1,175 cases) from FinnGen Data Freeze 2. A MR study was conducted to examine the effect of selected single nucleotide polymorphisms (SNPs) and OA, RA, and OP risk. Several sensitivity analyses were performed with weighted median and inverse-variance weighted methods for estimating the causal effects.ResultsIn this MR study, the genetically predicted per one cup increase of tea consumption was not associated with knee OA (OR 1.11,95% CI: 0.79–1.55) using IVW with random effect. Genetic predisposition to tea consumption was not associated with hip OA (OR: 1.20, 95% CI: 0.84–1.71), RA (OR: 1.24 95% CI: 0.81–1.91), and OP (OR: 1.11, 95% CI: 0.89, 1.39). Following the sensitivity analysis, there was no potential pleiotropy.ConclusionAccording to our study, According to our study, there was no statistical power to confirm a causal relationship between tea consumption and the risk of knee OA, hip OA, RA, and OP.

Associations of combined lifestyle and genetic risks with incident psoriasis: A prospective cohort study among UK Biobank participants of European ancestry

Whether the lifestyle is associated with the risk of psoriasis in the presence of different genetic risk levels remains unknown. To examine the gene-behavior interaction in association with incident psoriasis. This study is based on the data from the UK Biobank, which recruited 500,000 participants. Genetic risk was categorized into low, intermediate, and high groups. The lifestyle score comprised the body mass index, smoking, physical activity, and diet and was also categorized into the ideal, intermediate, and poor groups. Within each genetic risk group, the risks of incident psoriasis associated with each lifestyle level were investigated and compared with the low genetic risk and ideal lifestyle group. Compared with the low genetic risk and ideal lifestyle group, the poor lifestyle and high genetic risk group was associated with a hazard ratio of up to 4.625 (95% confidence interval [CI], 2.920-7.348) for psoriasis. There was no interaction between genetic risk and lifestyle. The population attributable fractions of lifestyle and genetic risk were 32.2% (95% CI, 25.1%-38.6%) and 13.0% (95% CI, 3.2%-21.8%), respectively. No verification in other independently ascertained populations. Lifestyle factors are predictive of the risk of incident psoriasis independent of genetic risk, and the relative impact of lifestyle factors was greater than that of genetic risk.

Inflammation subtypes in psychosis and their relationships with genetic risk for psychiatric and cardiometabolic disorders

Cardiometabolic disorders have known inflammatory implications, and peripheral measures of inflammation and cardiometabolic disorders are common in persons with psychotic disorders. Inflammatory signatures are also related to neurobiological and behavioral changes in psychosis. Relationships between systemic inflammation and cardiometabolic genetic risk in persons with psychosis have not been examined. Thirteen peripheral inflammatory markers and genome-wide genotyping were assessed in 122 participants (n ​= ​86 psychosis, n ​= ​36 healthy controls) of European ancestry. Cluster analyses of inflammatory markers classified higher and lower inflammation subgroups. Single-trait genetic risk scores (GRS) were constructed for each participant using previously reported GWAS summary statistics for the following traits: schizophrenia, bipolar disorder, major depressive disorder, coronary artery disease, type-2 diabetes, low-density lipoprotein, high-density lipoprotein, triglycerides, and waist-to-hip ratio. Genetic correlations across traits were quantified. Principal component (PC) analysis of the cardiometabolic GRSs generated six PC loadings used in regression models to examine associations with inflammation markers. Functional module discovery explored biological mechanisms of the inflammation association of cardiometabolic GRS genes. A subgroup of 38% persons with psychotic disorders was characterized with higher inflammation status. These higher inflammation individuals had lower BACS scores (p ​= ​0.038) compared to those with lower inflammation. The first PC of the cardiometabolic GRS matrix was related to higher inflammation status in persons with psychotic disorders (OR ​= ​2.037, p ​= ​0.001). Two of eight modules within the functional interaction network of cardiometabolic GRS genes were enriched for immune processes. Cardiometabolic genetic risk may predispose some individuals with psychosis to elevated inflammation which adversely impacts cognition associated with illness.

The age-dependent association of risk factors with pancreatic cancer

Pancreatic cancer presents as advanced disease in >80% of patients; yet, appropriate ages to consider prevention and early detection strategies are poorly defined. We investigated age-specific associations and attributable risks of pancreatic cancer for established modifiable and non-modifiable risk factors. We included 167 483 participants from two prospective US cohort studies with 1190 incident cases of pancreatic cancer during >30 years of follow-up; 5107 pancreatic cancer cases and 8845 control participants of European ancestry from a completed multicenter genome-wide association study (GWAS); and 248 893 pancreatic cancer cases documented in the US Surveillance, Epidemiology, and End Results (SEER) Program. Across different age categories, we investigated cigarette smoking, obesity, diabetes, height, and non-O blood group in the prospective cohorts; weighted polygenic risk score of 22 previously identified single nucleotide polymorphisms in the GWAS; and male sex and black race in the SEER Program. In the prospective cohorts, all five risk factors were more strongly associated with pancreatic cancer risk among younger participants, with associations attenuated among those aged >70 years. The hazard ratios comparing participants with three to five risk factors with those with no risk factors were 9.24 [95% confidence interval (CI) 4.11-20.77] among those aged ≤60 years, 3.00 (95% CI 1.85-4.86) among those aged 61-70 years, and 1.46 (95% CI 1.10-1.94) among those aged >70 years (Pheterogeneity= 3×10-5). These factors together were related to 65.6%, 49.7%, and 17.2% of incident pancreatic cancers in these age groups, respectively. In the GWAS and the SEER Program, the associations with the polygenic risk score, male sex, and black race were all stronger among younger individuals (Pheterogeneity ≤0.01). Established risk factors are more strongly associated with earlier-onset pancreatic cancer, emphasizing the importance of age at initiation for cancer prevention and control programs targeting this highly lethal malignancy.

Association of Genetic Variants Linked to Late-Onset Alzheimer Disease With Cognitive Test Performance by Midlife

Identifying the youngest age when Alzheimer disease (AD) influences cognition and the earliest affected cognitive domains will improve understanding of the natural history of AD and approaches to early diagnosis. To evaluate the age at which cognitive differences between individuals with higher compared with lower genetic risk of AD are first apparent and which cognitive assessments show the earliest difference. This cross-sectional study used data from UK Biobank participants of European genetic ancestry, aged 40 years or older, who contributed genotypic and cognitive test data from January 1, 2006, to December 31, 2015. Data analysis was performed from March 10, 2020, to January 4, 2022. The AD genetic risk score (GRS), which is a weighted sum of 23 single-nucleotide variations. Seven cognitive tests were administered via touchscreen at in-person visits or online. Cognitive domains assessed included fluid intelligence, episodic memory, processing speed, executive functioning, and prospective memory. Multiple cognitive measures were derived from some tests, yielding 32 separate measures. Interactions between age and AD-GRS for each of the 32 cognitive measures were tested with linear regression using a Bonferroni-corrected P value threshold. For cognitive measures with significant evidence of age by AD-GRS interaction, the youngest age of interaction was assessed with new regression models, with nonlinear specification of age terms. Models with youngest age of interaction from 40 to 70 years, in 1-year increments, were compared, and the best-fitting model for each cognitive measure was chosen. Results across cognitive measures were compared to determine which cognitive indicators showed earliest AD-related change. A total of 405 050 participants (mean [SD] age, 57.1 [7.9] years; 54.1% female) were included. Sample sizes differed across cognitive tests (from 12 455 to 404 682 participants). The AD-GRS significantly modified the association with age on 13 measures derived from the pairs matching (range in difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 2.5%-11.5%), symbol digit substitution (range in difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 2.0%-5.8%), and numeric memory tests (difference in mean cognition per decade increase in age for 1-SD higher AD-GRS, 8.8%) (P = 1.56 × 10-3). Best-fitting models suggested that cognitive scores of individuals with a high vs low AD-GRS began to diverge by 56 years of age for all 13 measures and by 47 years of age for 9 measures. In this cross-sectional study, by early midlife, subtle differences in memory and attention were detectable among individuals with higher genetic risk of AD.

A genome-wide association study of bronchodilator response in participants of European and African ancestry from six independent cohorts.

IntroductionBronchodilator response (BDR) is a measurement of acute bronchodilation in response to short-acting β2-agonists, with a heritability between 10 and 40%. Identifying genetic variants associated with BDR may lead to a better understanding of its complex pathophysiology.MethodsWe performed a genome-wide association study (GWAS) of BDR in six adult cohorts with participants of European ancestry (EA) and African ancestry (AA) including community cohorts and cohorts ascertained on the basis of obstructive pulmonary disease. Validation analysis was carried out in two paediatric asthma cohorts.ResultsA total of 10 623 EA and 3597 AA participants were included in the analyses. No single nucleotide polymorphism (SNP) was associated with BDR at the conventional genome-wide significance threshold (p<5×10−8). Performing fine mapping and using a threshold of p<5×10−6 to identify suggestive variants of interest, we identified three SNPs with possible biological relevance: rs35870000 (within FREM1), which may be involved in IgE- and IL5-induced changes in airway smooth muscle cell responsiveness; rs10426116 (within ZNF284), a zinc finger protein, which has been implicated in asthma and BDR previously; and rs4782614 (near ATP2C2), involved in calcium transmembrane transport. Validation in paediatric cohorts yielded no significant SNPs, possibly due to age–genotype interaction effects.ConclusionAncestry-stratified and ancestry-combined GWAS meta-analyses of over 14 000 participants did not identify genetic variants associated with BDR at the genome-wide significance threshold, although a less stringent threshold identified three variants showing suggestive evidence of association. A common definition and protocol for measuring BDR in research may improve future efforts to identify variants associated with BDR.

Assessing the impact of blood pressure in the development of inflammatory bowel disease.

The purpose of this study is to investigate the potential causal relationships between blood pressure and inflammatory bowel disease (IBD) by using the bidirectional Mendelian randomization (MR) approach. Summary‐level data for blood pressure was extracted from the hitherto largest genome‐wide study (GWAS) with 759 601 participants of European‐descent. We used 56 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for blood pressure. Summary statistics for IBD were derived from a GWAS with an overall 59 957 participants of European ancestry, of which 109 IVs were selected. Several robust analytical methods, including inverse‐variance weighted (IVW) method, weighted‐median method, MR‐Egger regression, MR‐PRESSO test, maximum likelihood method, “leave‐one‐out” and multivariable MR analysis were used to evaluate the causal associations between blood pressure and IBD. Genetically predicted higher systolic blood pressure (SBP) was associated with an increased risk of IBD (odds ratio (OR) = 1.05, 95% confidence interval (CI):1.02–1.08, P = .001 by IVW). Subgroup analysis showed that higher SBP was positively associated with Crohn's disease (CD) (OR = 1.06, 95% CI:1.03–1.09, P = 9.18 × 10−5) and ulcerative colitis (UC) (OR = 1.05, 95% CI:1.01–1.09, P = .017) risk, respectively. In reverse‐direction MR analysis, the authors observed no evidence for the causal effect of IBD on blood pressure. Our findings suggested that high SBP was associated with an increased risk of IBD (for both UC and CD). Further studies are required to clarify the underlying mechanism of this causal association.

Alcohol use and alcohol use disorder differ in their genetic relationships with PTSD: A genomic structural equation modelling approach

PurposePosttraumatic Stress Disorder (PTSD) is associated with increased alcohol use and alcohol use disorder (AUD), which are all moderately heritable. Studies suggest the genetic association between PTSD and alcohol use differs from that of PTSD and AUD, but further analysis is needed. Basic proceduresWe used genomic Structural Equation Modeling (genomicSEM) to analyze summary statistics from large-scale genome-wide association studies (GWAS) of European Ancestry participants to investigate the genetic relationships between PTSD (both diagnosis and re-experiencing symptom severity) and a range of alcohol use and AUD phenotypes. Main findingsWhen we differentiated genetic factors for alcohol use and AUD we observed improved model fit relative to models with all alcohol-related indicators loading onto a single factor. The genetic correlations (rG) of PTSD were quite discrepant for the alcohol use and AUD factors. This was true when modeled as a three-correlated-factor model (PTSD-AUD rG:.36, p < .001; PTSD-alcohol use rG: −0.17, p < .001) and as a Bifactor model, in which the common and unique portions of alcohol phenotypes were pulled out into an AUD-specific factor (rG with PTSD:.40, p < .001), AU-specific factor (rG with PTSD: −0.57, p < .001), and a common alcohol factor (rG with PTSD:.16, NS). Principal conclusionsThese results indicate the genetic architecture of alcohol use and AUD are differentially associated with PTSD. When the portions of variance unique to alcohol use and AUD are extracted, their genetic associations with PTSD vary substantially, suggesting different genetic architectures of alcohol phenotypes in people with PTSD.

Associations of genetic risk factors and air pollution with incident hypertension among participants in the UK Biobank study

The purposes of this study were to quantify the association of the combination of air pollution and genetic risk factors with hypertension and explore the interactions between air pollution and genetic risk. This study included 391,366 participants of European ancestry initially free from pre-existing hypertension in the UK Biobank. Exposure to ambient air pollutants, including particulate matter (PM2.5 PM2.5-10, and PM10), nitrogen dioxide (NO2) and nitrogen oxides (NOX), was estimated through land use regression modelling, and the associations between air pollutants and the incidence of hypertension were investigated using a Cox proportional hazards model adjusted for covariates. Furthermore, we established a polygenic risk score for hypertension and assessed the combined effect of genetic susceptibility and air pollution on incident hypertension. The results showed significant associations between the risk of hypertension and exposure to PM2.5 (hazard ratio [HR]: 1.41, 95% confidence interval [CI]: 1.29–1.53; per 10 μg/m3), PM10 (1.05, 1.00–1.09; per 10 μg/m3), and NOX (1.01, 1.01–1.02 per 10 μg/m3). Additive effects of PM2.5 and NOX exposure and genetic risk were observed. Compared to individuals with a low genetic risk and low air pollution exposure, participants with high air pollution exposure and a high genetic risk had a significantly increased risk of hypertension (PM2.5: 71% (66%–76%), PM10: 59% (55%–64%), NOX: 65% (60%–70%)). Our results indicate that long-term exposure to air pollution is associated with an increased risk of hypertension, especially in individuals with a high genetic risk.

Genome-wide association study meta-analysis identifies three novel loci for circulating anti-Müllerian hormone levels in women.

Genome-wide association study meta-analysis identifies three novel loci for circulating anti-Müllerian hormone levels in women.

Apolipoprotein A-V is a potential target for treating coronary artery disease: evidence from genetic and metabolomic analyses

Triglyceride (TG)-lowering LPL variants in combination with genetic LDL-C-lowering variants are associated with reduced risk of coronary artery disease (CAD). Genetic variation in the APOA5 gene encoding apolipoprotein A-V also strongly affects TG levels, but the potential clinical impact and underlying mechanisms are yet to be resolved. Here, we aimed to study the effects of APOA5 genetic variation on CAD risk and plasma lipoproteins through factorial genetic association analyses. Using data from 309,780 European-ancestry participants from the UK Biobank, we evaluated the effects of lower TG levels as a result of genetic variation in APOA5 and/or LPL on CAD risk with or without a background of reduced LDL-C. Next, we compared lower TG levels via APOA5 and LPL variation with over 100 lipoprotein measurements in a combined sample from the Netherlands Epidemiology of Obesity study (N = 4,838) and the Oxford Biobank (N = 6,999). We found that lower TG levels due to combined APOA5 and LPL variation and genetically-influenced lower LDL-C levels afforded the largest reduction in CAD risk (odds ratio: 0.78 (0.73–0.82)). Compared to patients with genetically-influenced lower TG via LPL, genetically-influenced lower TG via APOA5 had similar and independent, but notably larger, effects on the lipoprotein profile. Our results suggest that lower TG levels as a result of APOA5 variation have strong beneficial effects on CAD risk and the lipoprotein profile, which suggest apo A-V may be a potential novel therapeutic target for CAD prevention.

Ambient Air Pollutants and Traffic Factors Were Associated with Blood and Urine Biomarkers and Asthma Risk.

The UK Biobank (UKBB) is a large population-based cohort that provides a unique opportunity to study the association between environmental exposure and biomarkers and to identify biomarkers as potential instruments for assessing exposure dose, health damage, and disease risks. On 462 063 participants of European ancestry, we characterized the relationship of 38 disease-relevant biomarkers, asthma diagnosis, ambient pollution, traffic factors, and genetic background. The air pollutant exposure on the UKBB cohort was fairly low (e.g., mean PM2.5 concentration at 10.0 μg/m3). Nevertheless, 30 biomarkers were in association with at least one environmental factor; e.g., C-reactive protein levels were positively associated with NO (padj = 2.99 × 10-4), NO2 (padj = 4.15 × 10-4), and PM2.5 (padj = 1.92 × 10-6) even after multiple testing adjustment. Asthma diagnosis was associated with four pollutants (NO, NO2, PM2.5, and PM10). The largest effect size was observed in PM2.5, where a 5 μg/m3 increment of exposure was associated with a 1.52 increase in asthma diagnosis (p = 4.41 × 10-13). Further, environmental exposure and genetic predisposition influenced biomarker levels and asthma diagnosis in an additive model. The exposure-biomarker associations identified in this study could serve as potential indicators for environmental exposure induced health damages. Our results also shed light on possible mechanisms whereby environmental exposure influences disease-causing biomarkers and in turn increases disease risk.

The burden of rare protein-truncating genetic variants on human lifespan

Genetic predisposition has been shown to contribute substantially to the age at which we die. Genome-wide association studies (GWASs) have linked more than 20 loci to phenotypes related to human lifespan1. However, little is known about how lifespan is impacted by gene loss of function. Through whole-exome sequencing of 352,338 UK Biobank participants of European ancestry, we assessed the relevance of protein-truncating variant (PTV) gene burden on individual and parental survival. We identified four exome-wide significant (P < 4.2 × 10−7) human lifespan genes, BRCA1, BRCA2, ATM and TET2. Gene and gene-set, PTV-burden, phenome-wide association studies support known roles of these genes in cancer to impact lifespan at the population level. The TET2 PTV burden was associated with a lifespan through somatic mutation events presumably due to clonal hematopoiesis. The overlap between PTV burden and common variant-based lifespan GWASs was modest, underscoring the value of exome sequencing in well-powered biobank cohorts to complement GWASs for identifying genes underlying complex traits.

Abstract 015: Genome-wide Association Study Of Variant-by-thiazide Diuretic Interactions In The UK Biobank Identifies A Novel Locus For Thiazide-LDL-C Interaction

Introduction: Although thiazide diuretics are common therapies for the treatment of hypertension, evidence suggests that they are also associated with elevated blood lipid concentrations after their initiation. Pharmacogenomics studies could help identify potential biological pathways underlying this phenomenon, but few well-powered studies have been conducted. Methods: In participants of European ancestry from the UK Biobank, we conducted a genome-wide association study (GWAS) to examine whether common variants (minor allele frequency [MAF] &gt;1%) modified the effect of thiazide diuretic use on three lipid measures: low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) concentrations (mmol/L). TG concentrations were natural log transformed, and LDL-C concentrations were adjusted for statin use. Given the conflicting evidence about the impact of loop diuretics on blood lipid concentrations, unexposed participants were defined as those taking neither thiazides nor loop diuretics. GWAS of UK10K plus 1000-Genomes Phase 3 imputed data were performed using SAIGE, adjusting for age, sex, fasting status, body mass index, study center, and the first 10 ancestral principal components. Results: Approximately 7.1% (n=27,971) of participants (n=395,058; mean age=57 years; 54% female [n=214,334]) used thiazides at study baseline. The thiazide-LDL-C GWAS (n=9,680,686 variants) identified one chromosome 19 locus harboring several genome-wide significant variants that modified the effect of thiazide diuretic use on LDL-C. The lead variant rs2199576 (MAF = 0.18) had an effect estimate (standard error) of 0.159 (0.013) among participants exposed to thiazides, and an effect estimate of 0.083 (0.003) among participants unexposed to any diuretic, yielding a significant variant-by-thiazide interaction effect estimate of 0.076 (0.013) ( p = 1.62 x 10 -9 ). These effect estimates are comparable to previously identified main effects of blood lipids loci. The rs2199576 variant resides near the PVRL2 locus, a cholesterol-responsive gene that is located within 100 kb of TOMM40 and the APO cluster, which have both been associated with blood lipid concentrations and Alzheimer’s disease. Conclusion: Our results may provide insights into pathways that influence the adverse effects of thiazide diuretic use and highlight the large sample sizes needed to detect modest pharmacogenetic effects.

Abstract MP17: Multivariable Mendelian Randomization Identifies Heterogeneity In The Effects Of Individual Branched Chain Amino Acids Across Metabolic, Cardiovascular, And Cognitive Phenotypes

Introduction: Experimental and observational evidence suggests that aberrant branched chain amino acid (BCAA; leucine, isoleucine, and valine) metabolism promotes insulin resistance and downstream disease, prompting interest in BCAA catabolism as a treatment target. Most published research has evaluated the three BCAAs in combination, although each BCAA may harbor distinct phenotypic effects, as valine is glucogenic, leucine is ketogenic, and isoleucine is glucogenic and ketogenic. Methods: Because studies examining individual phenotypic effects of BCAAs that account for the effects of other BCAAs have been limited by high correlation between BCAAs and strong confounding by dietary patterns and shared genetic loci, we applied a novel causal inference method developed to address these limitations: multivariable Mendelian randomization (MVMR). In a study of UK Biobank European ancestry participants, we examined 1,468 phenotypes that included metabolic, cardiovascular, cancer, cognitive, hematopoietic, and musculoskeletal domains. Polygenic risk score (PRS) instrumental variables were constructed using genotypic and circulating BCAA phenotypic data in European ancestry UK Biobank participants and the Crosspred method was used to correct for overfitting. Significant independent causal effects were defined as estimates with P- values&lt; 1.1x10 -5 [0.05/(1,468 phenotypes*3 BCAAs)]. Results: The n=97,469 participants with measured BCAAs were on average middle aged (mean age=57), female (54%), and overweight [mean body mass index (BMI)=27]. Each BCAA PRS strongly predicted its circulating concentrations ( P- value&lt;10 -100 ). MVMR methods did not identify any phenotypes for which all three BCAAs showed evidence of a directionally consistent and significant independent causal effect. However, there were numerous instances where BCAAs harbored independent and directionally inconsistent statistically significant effects. For example, significant positive causal effects for valine independent of isoleucine and leucine and significant negative causal effects for leucine independent of valine and isoleucine were identified for BMI, glycated hemoglobin, and type 2 diabetes; no significant independent causal effects for isoleucine with BMI, glycated hemoglobin, and type 2 diabetes were identified. In contrast, models without control for the effects of other BCAAs suggested that isoleucine, leucine and valine each had significant positive causal effects on BMI, glycated hemoglobin, and type 2 diabetes. When examining other phenotypes using MVMR, heterogeneity in the effects of individual BCAAs was detected for cardiovascular and cognitive phenotypes, among others. Conclusion: BCAAs may harbor distinct and opposing effects on metabolism, health, and disease, motivating further studies that examine the independent effects of these essential amino acids.

Abstract P182: Large Scale Analyses Of Gene-by-smoking Interaction On Cardiovascular Disease

Introduction: Cardiovascular disease risk is determined by both genetic susceptibility and lifestyle factors such as smoking. However, gene-by-smoking interactions have been understudied in this context. The objective of this study was to leverage large-scale individual level data to carry out a genome-wide gene-by-smoking interaction analysis on cardiovascular outcomes including coronary heart disease (CHD), stroke and peripheral artery disease (PAD). Methods: Our study sample included 401,384 unrelated, European-ancestry participants of the UK Biobank study. CHD, stroke, and PAD outcomes were based on data from baseline questionnaires and linked data from inpatient admissions and death registries. Smoking status (ever vs never) was based on self-report at baseline. Gene-environment interaction analyses were carried out using GEM (https://github.com/large-scale-gxe-methods/GEM), a new, computationally efficient software tool developed for biobank scale data. Using generalized linear models, we carried out a test of the genetic main effect adjusted for smoking status, a formal test for gene-by-smoking interaction, and a joint test of the main genetic and interaction effects. Single nucleotide polymorphisms with a minor allele frequency less than 1% were excluded from analyses. Results: The formal interaction test revealed a novel genome-wide significant (GWS) gene-by-smoking signal for PAD within the IREB2 gene (p=2.0x10 -8 ), which has been previously associated with smoking intensity and lung disease. The joint test has been shown to increase power for genetic discovery, which we observed here. The joint test for PAD identified 10 additional loci reaching genome-wide significance (p&lt;5x10 -8 ) that were not revealed in the main effect analyses. Several of these loci are in genes linked with measures of body composition in earlier studies ( PNLIP, CDH4, STAT5A, PRKCE ). We did not detect any GWS gene-by-smoking interactions for CHD or stroke. However, for CHD, two novel loci within the ARSG and SARS1 genes were identified using the joint test but had no GWS main effects. Both genes have been associated with LDL-cholesterol levels in prior genome-wide studies. Although our analyses did not yield any signals that exceeded the GWS threshold for stroke, we did identify 25 and 47 independent loci that reached genome-wide suggestive significance (p&lt;1x10 -5 ) for the formal interaction and joint tests, respectively. We are augmenting the current analyses to include additional data from approximately 120,000 trans-ethnic ancestry individuals. Conclusion: The analysis of gene-by-smoking interactions can provide novel insights into the genetic architecture and pathophysiology of cardiovascular disease.

Association of smoking and polygenic risk with the incidence of lung cancer: a prospective cohort study

BackgroundGenetic variation increases the risk of lung cancer, but the extent to which smoking amplifies this effect remains unknown. Therefore, we aimed to investigate the risk of lung cancer in people with different genetic risks and smoking habits.MethodsThis prospective cohort study included 345,794 European ancestry participants from the UK Biobank and followed up for 7.2 [6.5–7.8] years.ResultsOverall, 26.2% of the participants were former smokers, and 9.8% were current smokers. During follow-up, 1687 (0.49%) participants developed lung cancer. High genetic risk and smoking were independently associated with an increased risk of incident lung cancer. Compared with never-smokers, HR per standard deviation of the PRS increase was 1.16 (95% CI, 1.11–1.22), and HR of heavy smokers (≥40 pack-years) was 17.89 (95% CI, 15.31–20.91). There were no significant interactions between the PRS and the smoking status or pack-years. Population-attributable fraction analysis showed that smoking cessation might prevent 76.4% of new lung cancers.ConclusionsBoth high genetic risk and smoking were independently associated with higher lung cancer risk, but the increased risk of smoking was much more significant than heredity. The combination of traditional risk factors and additional PRS provides realistic application prospects for precise prevention.

Non-alcoholic fatty liver disease and stroke: A Mendelian randomization study.

The association between non-alcoholic fatty liver disease (NAFLD) and the risk of stroke is heterogeneous. Therefore, we aimed to examine any potential causal relationship between these two traits through Mendelian randomization. The genetic instruments associated with NAFLD were selected from a large genome-wide association study in individuals of European ancestry (1483 cases and 17,781 controls, replicated in 559 cases and 945 controls). The genetic associations for stroke (40,585 cases and 406,111 controls) and ischemic stroke (34,217 cases and 406,111 controls) were selected from the MEGASTROKE consortium of European ancestry participants. The causal effects on ischemic stroke subtypes, including large artery atherosclerosis (LAA) (4373 cases and 146,392 controls), small vessel occlusion (SVO) (5386 cases and 192,662 controls), and cardioembolic stroke (7193 cases and 204,570 controls), were also analyzed. The inverse variant weighted method was performed to obtain the casual estimates. Heterogeneity and pleiotropy of individual single nucleotide polymorphisms were also tested for the robustness of the results. NAFLD was not associated with stroke (odds ratio [OR] 1.015; 95% confidence interval [CI] 0.996-1.034; p=0.121) and ischemic stroke (OR 1.017; 95% CI 0.997-1.037; p=0.092). Regarding ischemic stroke subtypes, there were positive causal inferences on LAA (OR 1.065; 95% CI 1.004-1.129; p=0.037) and SVO (OR 1.058; 95% CI 1.003-1.116; p=0.037), while it was not significant for cardioembolic stroke (OR 1.026; 95% CI 0.983-1.071; p=0.243). This study suggests that the potential causal effect of NAFLD on ischemic stroke may be confined to the LAA and SVO subtypes.

Interaction between genetics and smoking in determining risk of coronary artery diseases.

Coronary artery disease (CAD) is a preeminent cause of death, and smoking is a strong risk factor for CAD. Genetic factors contribute to the development of CAD, but the interplay between genetic predisposition and smoking history in CAD remains unclear. Using data from the UK Biobank, we constructed several genetic risk scores (GRSs) based on known CAD loci and assessed their interactions with smoking for the development of incident CAD in 307,147 participants of European ancestry who were free of CAD. We fitted Cox proportional hazard models and assessed gene-smoking interaction on both multiplicative and additive scales. Overall, we found no multiplicative interactions, but observed a synergistic additive interaction of GRS with both smoking status and pack-years of smoking, finding that the absolute CAD risk due to smoking was higher for those with high genetic risk. Trait-based sub-GRSs suggested smoking status and smoking intensity measured by pack-years might confer gene-smoking interaction effects with different intermediate risk factors for CAD. Our study results suggest that genetics could modify the effects of smoking on CAD and highlight the value of addressing gene-lifestyle interactions on both additive and multiplicative scales.