Independent Genetic Variants Research Articles

Effects of depression on employment and social outcomes: a Mendelian randomisation study

BackgroundDepression is associated with socioeconomic disadvantage. However, whether and how depression exerts a causal effect on employment remains unclear. We used Mendelian randomisation (MR) to investigate whether depression affects employment...

Adiposity, diabetes, lifestyle factors and risk of gastroesophageal reflux disease: a Mendelian randomization study

Adiposity, diabetes, and lifestyle factors are linked to gastroesophageal reflux disease (GERD) in observational studies. We conducted a two-sample Mendelian randomization analysis to determine whether those associations are causal. Independent genetic variants associated with body mass index (BMI), waist circumference (with and without adjustment for BMI), type 2 diabetes, smoking, and alcohol, coffee and caffeine consumption at the genome-wide significance level were selected as instrumental variables. Summary-level data for GERD were available from a genome-wide association meta-analysis of 71,522 GERD cases and 261,079 controls of European descent from the UK Biobank and QSkin Sun and Health studies. The odds ratio (OR) of GERD was 1.49 (95% confidence interval (CI), 1.40–1.60) for one standard deviation (SD) increase in BMI, 1.07 (95% CI, 1.04–1.10) for one-unit increase in log-transformed OR of type 2 diabetes, and 1.41 (95% CI, 1.31–1.52) for one SD increase in prevalence of smoking initiation. There were suggestive associations with GERD for higher genetically predicted waist circumference (OR per one SD increase, 1.14, 95% CI, 1.02–1.26) and caffeine consumption (OR per 80 mg increase, 1.08, 95% CI, 1.02–1.15). Genetically predicted waist circumference adjusted for BMI, alcohol or coffee consumption was not associated GERD. This study suggests causal roles of adiposity, diabetes, and smoking, and a possible role of high caffeine consumption in the development of GERD.

Genetic Loci Associated With COVID-19 Positivity and Hospitalization in White, Black, and Hispanic Veterans of the VA Million Veteran Program.

SARS-CoV-2 has caused symptomatic COVID-19 and widespread death across the globe. We sought to determine genetic variants contributing to COVID-19 susceptibility and hospitalization in a large biobank linked to a national United States health system. We identified 19,168 (3.7%) lab-confirmed COVID-19 cases among Million Veteran Program participants between March 1, 2020, and February 2, 2021, including 11,778 Whites, 4,893 Blacks, and 2,497 Hispanics. A multi-population genome-wide association study (GWAS) for COVID-19 outcomes identified four independent genetic variants (rs8176719, rs73062389, rs60870724, and rs73910904) contributing to COVID-19 positivity, including one novel locus found exclusively among Hispanics. We replicated eight of nine previously reported genetic associations at an alpha of 0.05 in at least one population-specific or the multi-population meta-analysis for one of the four MVP COVID-19 outcomes. We used rs8176719 and three additional variants to accurately infer ABO blood types. We found that A, AB, and B blood types were associated with testing positive for COVID-19 compared with O blood type with the highest risk for the A blood group. We did not observe any genome-wide significant associations for COVID-19 severity outcomes among those testing positive. Our study replicates prior GWAS findings associated with testing positive for COVID-19 among mostly White samples and extends findings at three loci to Black and Hispanic individuals. We also report a new locus among Hispanics requiring further investigation. These findings may aid in the identification of novel therapeutic agents to decrease the morbidity and mortality of COVID-19 across all major ancestral populations.

Abstract TMP22: Genetic Predisposition To Cardiovascular Disease Is Associated With Higher Risk Of Stroke In Persons With COVID-19

Background and Purpose: Stroke is a serious complication of COVID-19. However, the risk factors for this complication are poorly understood. We hypothesize that genetic predisposition to cardio- and cerebrovascular disease (CVD) leads to an increased risk of stroke in patients with COVID-19 infection. Methods: We evaluated data from a nested cohort study conducted within the UK Biobank focused on persons with documented COVID-19. Incident strokes (ischemic and hemorrhagic) were identified by combining inpatient data (including critical care and discharge diagnostic codes) and primary care data, the latter entered by providers within 30 days of a positive COVID-19 test. Genetic predisposition to CVD was evaluated through a polygenic risk score that integrated genomic information on 2,176 independent genetic risk variants for stroke, coronary artery disease and cardiometabolic risk factors. This score was divided into low (0-20 th percentile), intermediate (20 th -80 th percentile), and high (80 th -100 th percentile) genetic risk. Results: A total of 11,882 study participants (mean age 65.8, SD [8.6], female sex 6,306 [53.1%]) with documented COVID-19 infection were included in this study, including 99 (0.8%) persons that sustained a stroke during the infection. Compared to persons with low genetic predisposition to CVD, those with intermediate and high genetic risk had 35% (OR 1.35, 95%CI 1.14-1.55) and 2.4-fold (OR 2.38, 95% CI 1.71-3.05) higher risk of stroke (test for trend p=0.004). Sub-scoring analyses evaluating one polygenic risk score per CVD trait of interest indicated that genetic predisposition to hypertension (p=0.017) and smoking (p=0.03) were the most important genetic risk factors. Conclusions: Genetic predisposition to CVD is associated with a higher risk of stroke in persons with acute COVID-19 infection. Genetic risk factors for hypertension and smoking appear to mediate a significant portion of this association. Genetic information should be considered in the multiple ongoing efforts to create risk-stratification strategies to identify COVID-19 patients at high risk of stroke.

Abstract 105: Polygenic Burden Of Hypertension-related Alleles Leads To Non-traumatic Subarachnoid Hemorrhage At Younger Ages

Introduction: Non-traumatic subarachnoid hemorrhage (SAH) is strongly linked to hypertension, a condition highly influenced by common genetic variants. For complex diseases influenced by genetic and environmental factors, genetic predisposition plays a key role in earlier onset. We tested the hypothesis that persons with a higher polygenic burden of hypertension-related alleles have SAH at younger ages. Methods: We analyzed data from the UK Biobank, a large cohort study that enrolled over 500,000 Britons aged 40-69. We included participants of European descent. We constructed two polygenic risk scores (PRS) using 807 independent genetic variants known to associate with higher systolic and diastolic blood pressure (BP). We fitted linear regression to assess the relationship between these PRS and the age-of-onset of SAH, using product terms to test for interaction with sex. We subsequently implemented Mendelian Randomization analyses using the inverse variance weighted and weighted median methods to evaluate causality. Results: We evaluated a total of 1,178 SAH cases (mean age, 58; female sex, 722 [61.3%]). When evaluating all participants jointly, there was no association between the systolic BP PRS and age-of-onset for SAH (p=0.130). There was a significant interaction between the PRS and sex (p=0.002): each additional standard deviation of the systolic BP PRS was associated with an earlier onset of SAH in females (beta, -1.45; 95% CI, -2.31 to -0.58; p=0.001), but not in males (adjusted beta, 0.83; 95% CI, -0.37 to 2.02; p=0.176). In MR analyses, a 10mmHg increase in genetically determined systolic BP was associated with a 5-year earlier onset of SAH in female participants using both the inverse variance weighted (beta, -4.72; 95% CI, -7.34 to -2.10; p<0.001) and weighted median approaches (beta, -5.05; 95% CI, -9.19 to -0.90; p=0.017). Analyses with the diastolic BP SNPs yielded comparable results (all p<0.05). Conclusions: Genetically determined hypertension is associated with earlier onset of non-traumatic SAH in women. These results indicate that genetic predisposition may play a more important causal role in younger patients and point to genetic information as possible tools for early identification of high-risk individuals.

Abstract WP191: Genetic Analyses Support A Causal Role Of Lung Cancer In Ischemic Stroke

Introduction: Lung cancer has been linked to increased risk of thromboembolic events, including stroke. However, a causal relationship between lung cancer and ischemic stroke (IS) has yet to be established. Methods: We conducted a two-stage study using observational and genetic data from the UK Biobank, a large cohort study that enrolled over 500,000 Britons aged 40-69. We included participants of European descent. In Stage I, we used logistic regression to test the association between self-reported / ICD-defined lung cancer and risk of IS. In Stage II, we constructed a polygenic risk score (PRS) using 31 independent genetic variants known to associate with lung cancer, fitted logistic regression to assess the relationship between this PRS and risk of IS, and implemented the inverse variance weighted method of Mendelian randomization (MR). We tested for horizontal pleiotropy using the MR-Egger and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) approaches. Results: Out of 409,629 participants of European descent enrolled in the UK Biobank, there were 5,060 IS cases (mean age, 61.6 [standard deviation 6.5]; female sex, 1813 [35.8%]). The prevalence of lung cancer was 1.9% (n=94) and 0.5% (n=1,961) among persons with and without IS, respectively (unadjusted p<0.001). In multivariable analyses, self-reported / ICD-defined lung cancer was associated with a 54% increase in risk of IS (adjusted OR, 1.54; 95% CI, 1.30-1.81; p<0.001). Genetic analyses supported a causal link between lung cancer and IS. In PRS analysis, each additional standard deviation of the lung cancer-related PRS was associated with a 3% increase in risk of IS (adjusted OR, 1.03; 95% CI, 1.01-1.06; p=0.018). In MR analysis, genetically determined lung cancer was associated with a 5% increase in risk of IS (OR, 1.05; 95% CI, 1.01-1.09; p=0.022). There was no significant horizontal pleiotropy (MR-Egger intercept p=0.663; MR-PRESSO global test p=0.993). Conclusions: Genetically determined lung cancer is associated with increased risk of ischemic stroke. These findings provide evidence for a causal link between lung cancer and ischemic stroke. Further studies are needed to identify the biological pathways that mediate this link.

POS-343 BODY MASS INDEX AND DIABETIC NEPHROPATHY: A MENDELIAN RANDOMIZATION STUDY

The association between obesity and diabetic nephropathy (DN) has been studied but the results of these epidemiological studies are not entirely consistent. The causal effect of body mass index (BMI) on DN and kidney traits in type 2 diabetes was evaluated by a two-sample Mendelian randomization (MR) analysis. A total of 59 independent genetic variants were selected as instrumental variables for BMI in 158,284 participants from Biobank Japan, and their effects on DN risk, eGFR and proteinuria were estimated in 3972 Chinese individuals with type 2 diabetes. Then, subgroup analysis was performed with different BMI levels or sex. In addition, the sensitivity analyses were performed including MR-Egger regression for detecting genetic directional pleiotropic effects, and power calculation for evaluating the reliability of the study. The generalized summary-data-based MR (GSMR) method showed that a one standard deviation increase in BMI was causally associated with a 3-fold increase in the risk of DN (odds ratio [OR], 4.05; 95% confidence interval [95% CI], 2.10 to 7.82; P<0.001), and a 35% decrease of eGFR level (OR, 0.65; 95% CI, 0.54 to 0.78; P<0.001). However, BMI was not associated with the level of proteinuria (OR, 1.26; 95% CI, 0.89 to 1.79; P=0.19). In addition, subgroup analysis showed a positive association between BMI and the risk of DN in individuals with different BMI levels (BMI≥25 vs BMI<25 kg/m2) or sex. Analyses stratified by sex indicated the casual effect of BMI on DN was stronger in women (OR, 9.82; 95% CI, 1.83 to 52.67; P=0.008) than in men (OR, 3.39; 95% CI, 1.23 to 9.34; P=0.02). In sensitivity analyses, the MR-Egger regression intercepts indicated that the results were less likely to be affected by pleiotropy. Based on 1,314 DN cases and 2,658 controls, our study had ≥80% power to detect the causal effect of BMI on DN risk if the genuine OR≥1.69 per standard deviation increase of BMI. Genetic evidence showed that higher BMI levels was causally associated with increased risk of DN and decreased eGFR level, but not with proteinuria. The DN risk for women was more susceptible to BMI levels than men.

Inverse Association Between Serum 25-Hydroxyvitamin D and Nonalcoholic Fatty Liver Disease

Serum 25-hydroxyvitamin D [S-25(OH)D] and nonalcoholic fatty liver disease (NAFLD) are correlated in many observational studies, whereas the causality of this association is uncertain, especially in European populations. We conducted a bidirectional Mendelian randomization study to determine the association between S-25(OH)D and NAFLD. Seven and 6 independent genetic variants associated with S-25(OH)D and NAFLD at the genome-wide-significance level, respectively, were selected as instrumental variables. Summary-level data for S-25(OH)D were obtained from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits consortium including 79,366 individuals. Summary-level data for NAFLD were available from a genome-wide association meta-analysis (1483 cases and 17,781 controls), the FinnGen consortium (894 cases and 217,898 controls), and the UK Biobank study (275 cases and 360,919 controls). Summary-level data for 4 liver enzymes were obtained from the UK Biobank. There were genetic correlations of S-25(OH)D with NAFLD and certain liver enzymes. Genetically predicted higher levels of S-25(OH)D were consistently associated with a decreased risk of NAFLD in the 3 sources. For a 1-SD increase in genetically predicted S-25(OH)D levels, the combined odds ratio of NAFLD was 0.78 (95% confidence interval [CI], 0.69 to 0.89). Genetically predicted higher levels of S-25(OH)D showed a borderline association with aspartate aminotransferase levels (change -1.17; 95% CI, -1.36 to 0.01). Genetic predisposition to NAFLD was not associated with S-25(OH)D (change 0.13; 95% CI, -1.26 to 0.53). Our findings have clinical implications as they suggest that increased vitamin D levels may play a role in NAFLD prevention in European populations.

Mendelian randomization highlights significant difference and genetic heterogeneity in clinically diagnosed Alzheimer\u2019s disease GWAS and self-report proxy phenotype GWAX

BackgroundUntil now, Mendelian randomization (MR) studies have investigated the causal association of risk factors with Alzheimer’s disease (AD) using large-scale AD genome-wide association studies (GWAS), GWAS by proxy (GWAX), and meta-analyses of GWAS and GWAX (GWAS+GWAX) datasets. However, it currently remains unclear about the consistency of MR estimates across these GWAS, GWAX, and GWAS+GWAX datasets.MethodsHere, we first selected 162 independent educational attainment genetic variants as the potential instrumental variables (N = 405,072). We then selected one AD GWAS dataset (N = 63,926), two AD GWAX datasets (N = 314,278 and 408,942), and three GWAS+GWAX datasets (N = 388,324, 455,258, and 472,868). Finally, we conducted a MR analysis to evaluate the impact of educational attainment on AD risk across these datasets. Meanwhile, we tested the genetic heterogeneity of educational attainment genetic variants across these datasets.ResultsIn AD GWAS dataset, MR analysis showed that each SD increase in years of schooling (about 3.6 years) was significantly associated with 29% reduced AD risk (OR=0.71, 95% CI: 0.60–0.84, and P=1.02E−04). In AD GWAX dataset, MR analysis highlighted that each SD increase in years of schooling significantly increased 84% AD risk (OR=1.84, 95% CI: 1.59–2.13, and P=4.66E−16). Meanwhile, MR analysis suggested the ambiguous findings in AD GWAS+GWAX datasets. Heterogeneity test indicated evidence of genetic heterogeneity in AD GWAS and GWAX datasets.ConclusionsWe highlighted significant difference and genetic heterogeneity in clinically diagnosed AD GWAS and self-report proxy phenotype GWAX. Our MR findings are consistent with recent findings in AD genetic variants. Hence, the GWAX and GWAS+GWAX findings and MR findings from GWAX and GWAS+GWAX should be carefully interpreted and warrant further investigation using the AD GWAS dataset.

Investigating the Causal Relationship Between Physical Activity and Chronic Back Pain: A Bidirectional Two-Sample Mendelian Randomization Study.

Background: Recent observational studies have reported a negative association between physical activity and chronic back pain (CBP), but the causality of the association remains unknown. We introduce bidirectional Mendelian randomization (MR) to assess potential causal inference between physical activity and CBP. Materials and Methods: This two-sample MR used independent genetic variants associated with physical activity and CBP as genetic instruments from large genome-wide association studies (GWASs). The effects of both directions (physical activity to CBP and CBP to physical activity) were examined. Inverse variance-weighted meta-analysis and alternate methods (weighted median and MR-Egger) were used to combine the MR estimates of the genetic instruments. Multiple sensitivity analyses were conducted to examine the robustness of the results. Results: The MR set parallel GWAS cohorts, among which, those involved in the primary analysis were comprised of 337,234 participants for physical activity and 158,025 participants (29,531 cases) for CBP. No evidence of a causal relationship was found in the direction of physical activity to CBP [odds ratio (OR), 0.98; 95% CI, 0.85–1.13; p = 0.81]. In contrast, a negative causal relationship in the direction of CBP to physical activity was detected (β = −0.07; 95% CI, −0.12 to −0.01; p = 0.02), implying a reduction in moderate-vigorous physical activity (approximately 146 MET-minutes/week) for participants with CBP relative to controls. Conclusion: The negative relationship between physical activity and CBP is probably derived from the reduced physical activity of patients experiencing CBP rather than the protective effect of physical activity on CBP.

Abstract 10714: The Role of Interleukin-6 in Heart Failure and Its Subtypes: Results from Mendelian Randomization and Mediation Analysis

Introduction: Heart failure (HF) increases morbidity, mortality, and costs, with complex pathogenic mechanisms. Interleukin-6 (IL-6) is a key cytokine and immune regulator with broad impact on inflammation – a critical component of HF pathophysiology. Circulating levels of IL-6 receptor (IL-6R) determines the activity of the IL-6 signaling pathway. We aim to estimate the causal effect of the IL-6R on HF and two clinical subtypes: HF with reduced (HFrEF) and preserved ejection fraction (HFpEF) in a Mendelian Randomization (MR) framework including mediators. Hypothesis: Plausible causal associations between IL-6R and HF, HFrEF and HFpEF are mediated by body mass index (BMI) or coronary artery disease (CAD). Methods: Two-sample MR analyses were conducted using genetic association results for composite HF, HFrEF and HFpEF among &gt;300,000 MVP participants of European ancestry. Thirty-four independent genetic variants within 250 kb from the IL6R gene associated with plasma IL-6R levels were used as genetic instrumental variables. We estimated the direct effect of IL-6R levels on HF and subtypes, and the indirect effect mediated through BMI and CAD. Results: Causal effects of IL-6R on composite HF, HFrEF and HFpEF were estimated as odds ratios (OR): 0.97 (CI 0.96-0.99, p=0.02), 0.96 (CI 0.93-0.98, p=0.003) and 1.00 (CI 0.97-1.03, p=0.89), respectively. Mediation analyses for composite HF and HFrEF showed significant mediation effects by CAD, with ORs 0.98 (CI 0.97-0.99) and 0.98 (CI 0.96-1.00), respectively. No mediation effect of BMI was identified. Conclusions: These findings support a causal role of IL-6 signaling in composite HF and HFrEF, but not HFpEF. Although the IL-6 signaling pathway plays a role in both BMI and CAD, the effect of IL-6 signaling on composite HF and HFrEF may be mediated through by CAD. Our findings demonstrate the role of IL-6 signaling in HF and its difference between HF subtypes, which may lead to more specific therapeutic targets for HF.

Depression and Inflammatory Bowel Disease: A Bidirectional Two-sample Mendelian Randomization Study.

Observational studies have suggested a bidirectional association between depression and inflammatory bowel disease [IBD], including Crohn's disease [CD] and ulcerative colitis [UC]. However, it remains unclear whether the observed associations are causal due to the difficulties of determining sequential temporality. We investigated the association between depression and IBD by using bidirectional two-sample Mendelian randomization [MR]. Independent genetic variants for depression and IBD were selected as instruments from published genome-wide association studies [GWAS] among individuals of predominantly European ancestry. Summary statistics for instrument-outcome associations were retrieved from three separate databases for both depression [Psychiatric Genomics Consortium, FinnGen and UK Biobank] and IBD [the largest GWAS meta-analysis, FinnGen and UK Biobank], respectively. MR analyses included the inverse-variance-weighted method, weighted-median estimator, MR-Egger regression, and sensitivity analyses of Steiger filtering and MR PRESSO. From either direction, analyses were performed per outcome database and were subsequently meta-analysed using a fixed-effect model. Genetically predicted depression [per log-odds ratio increase] was associated with a higher risk of IBD; odds ratios [95% confidence interval] for IBD, CD and UC were 1.20 [1.05, 1.36], 1.29 [1.07, 1.56] and 1.22 [1.01, 1.47] in a combined sample size of 693 183 [36 507 IBD cases], 212 172 [13 714 CD cases] and 219 686 [15 691 UC cases] individuals, respectively. In contrast, no association was observed between genetically influenced IBD and depression in 534 635 individuals [71 466 depression cases]. Our findings corroborated a causal association of depression on IBD, which may impact the clinical decision on the management of depression in patients with IBD. Though our results did not support a causal effect of IBD on depression, further investigations are needed to clarify the effect of IBD activity on depression [with different symptomology].

Genetic Variants Associated With Human Eye Size Are Distinct From Those Conferring Susceptibility to Myopia.

PurposeEmmetropization requires coordinated scaling of the major ocular components, corneal curvature and axial length. This coordination is achieved in part through a shared set of genetic variants that regulate eye size. Poorly coordinated scaling of corneal curvature and axial length results in refractive error. We tested the hypothesis that genetic variants regulating eye size in emmetropic eyes are distinct from those conferring susceptibility to refractive error.MethodsA genome-wide association study (GWAS) for corneal curvature in 22,180 adult emmetropic individuals was performed as a proxy for a GWAS for eye size. A polygenic score created using lead GWAS variants was tested for association with corneal curvature and axial length in an independent sample: 437 classified as emmetropic and 637 as ametropic. The genetic correlation between eye size and refractive error was calculated using linkage disequilibrium score regression for approximately 1 million genetic variants.ResultsThe GWAS for corneal curvature in emmetropes identified 32 independent genetic variants (P < 5.0e-08). A polygenic score created using these 32 genetic markers explained 3.5% (P < 0.001) and 2.0% (P = 0.001) of the variance in corneal curvature and axial length, respectively, in the independent sample of emmetropic individuals but was not predictive of these traits in ametropic individuals. The genetic correlation between eye size and refractive error was close to zero (rg = 0.00; SE = 0.06; P = 0.95).ConclusionsThese results support the hypothesis that genetic variants regulating eye size in emmetropic eyes do not overlap with those conferring susceptibility to myopia. This suggests that distinct biological pathways regulate normal eye growth and myopia development.

Coffee and Caffeine Consumption and Risk of Kidney Stones: A Mendelian Randomization Study

Coffee and caffeine consumption have been associated with a lower risk of kidney stones in observational studies. We conducted a Mendelian randomization study to assess the causal nature of these associations. Mendelian randomization analysis. Independent genetic variants associated with coffee and caffeine consumption at the genome-wide significance level were selected from previously published meta-analyses as instrumental variables. Summary-level data for kidney stones were obtained from the UK Biobank study (6,536 cases and 388,508 noncases) and the FinnGen consortium (3,856 cases and 172,757 noncases). Genetically predicted coffee and caffeine consumption. Clinically diagnosed kidney stones. Mendelian randomization methods were used to calculate causal estimates. Estimates from the 2 sources were combined using the fixed-effects meta-analysis methods. Genetically predicted coffee and caffeine consumption was associated with a lower risk of kidney stones in the UK Biobank study, and the associations were directionally similar in the FinnGen consortium. The combined odds ratio of kidney stones was 0.60 (95% CI, 0.46-0.79; P< 0.001) per a genetically predicted 50% increase in coffee consumption and 0.81 (95% CI, 0.69-0.94; P= 0.005) per a genetically predicted 80-mg increase in caffeine consumption. Genetic influence on kidney stone risk via pathways not involving coffee or caffeine. Using genetic data, this study provides evidence that higher coffee and caffeine consumption may cause a reduction in kidney stones.

Mendelian randomization study of coffee consumption and age at onset of Huntington's disease

The association between habitual coffee or caffeine consumption and age at onset (AAO) of Huntington's disease (HD) is unclear. We employed Mendelian randomization to investigate the causal relationship between coffee consumption and AAO of HD. The instrumental variable including 14 independent genetic variants associated with coffee consumption was selected from a genome-wide association study (GWAS) meta-analysis of 375,833 individuals of European ancestry. Genetic association estimates for AAO of HD were obtained from the Genetic Modifiers of Huntington's Disease Consortium GWAS meta-analysis including 9064 HD patients of European ancestry. The inverse variance weighted method was used to evaluate the causal estimate and a comprehensive set of analyses tested the robustness of our results. Genetically predicted higher coffee consumption was associated with an earlier AAO of HD (β=-1.84 years, 95% confidence interval=-3.47 to-0.22, P=0.026). Results were robust to potential pleiotropy and weak instrument bias. This genetic study suggests high coffee consumption is associated with an earlier AAO of HD. Coffee is widely consumed and thus our findings, if confirmed, offers a potential way to delay the onset of this debilitating autosomal dominant disease.

Assigning Co-Regulated Human Genes and Regulatory Gene Clusters.

Elucidating the role of genetic variation in the regulation of gene expression is key to understanding the pathobiology of complex diseases which, in consequence, is crucial in devising targeted treatment options. Expression quantitative trait locus (eQTL) analysis correlates a genetic variant with the strength of gene expression, thus defining thousands of regulated genes in a multitude of human cell types and tissues. Some eQTL may not act independently of each other but instead may be regulated in a coordinated fashion by seemingly independent genetic variants. To address this issue, we combined the approaches of eQTL analysis and colocalization studies. Gene expression was determined in datasets comprising 49 tissues from the Genotype-Tissue Expression (GTEx) project. From about 33,000 regulated genes, over 14,000 were found to be co-regulated in pairs and were assembled across all tissues to almost 15,000 unique clusters containing up to nine regulated genes affected by the same eQTL signal. The distance of co-regulated eGenes was, on average, 112 kilobase pairs. Of 713 genes known to express clinical symptoms upon haploinsufficiency, 231 (32.4%) are part of at least one of the identified clusters. This calls for caution should treatment approaches aim at an upregulation of a haploinsufficient gene. In conclusion, we present an unbiased approach to identifying co-regulated genes in and across multiple tissues. Knowledge of such common effects is crucial to appreciate implications on biological pathways involved, specifically when a treatment option targets a co-regulated disease gene.

649Personal history of keratinocyte carcinoma is a marker of inherited cancer risk: Mendelian randomization analyses

Abstract Background A personal history of keratinocyte carcinoma (KC) has been reported as a risk factor for developing subsequent primary cutaneous and non-cutaneous malignancies. However most evidence to date stems from observational studies which are prone to bias, confounding and reverse causation. Our aim was to examine this association using different Mendelian randomization (MR) approaches. Methods We performed a one-sample MR analysis using individual-level data from the UK Biobank (n = 394,306). This analysis was then validated in an independent dataset in the QSkin cohort (n = 16,896). Using 64 independent genetic variants known to be associated with KC, we generated a polygenic risk score (PRS) for each participant in the UK Biobank and the QSkin cohort. We then performed two-sample MR analyses using genome-wide association study (GWAS) summary statistics. We tested the association between genetically predicted KC and risk of subsequent cancer using logistic regression. Results Results from one-sample MR analyses in the UK Biobank indicated that a personal history of KC was significantly associated with cancer overall (excluding melanoma) (OR: 1.15, 95% CI: 1.10-1.20, per doubling the prevalence of KC). The results from the two-sample MR corroborate the findings from the one-sample MR, although the risk estimate was lower (OR: 1.05, 95% CI: 1.03-1.07). Conclusions Our MR analyses suggest that genetically predicted KC is a risk factor for developing subsequent primary malignancies. Key messages A personal history of KC may serve as a proxy marker of inherited cancer risk.

Evaluating the Causal Association Between Educational Attainment and Asthma Using a Mendelian Randomization Design.

Asthma is a common chronic respiratory disease. In the past 10 years, genome-wide association study (GWAS) has been widely used to identify the common asthma genetic variants. Importantly, these publicly available asthma GWAS datasets provide important data support to investigate the causal association of kinds of risk factors with asthma by a Mendelian randomization (MR) design. It is known that socioeconomic status is associated with asthma. However, it remains unclear about the causal association between socioeconomic status and asthma. Here, we selected 162 independent educational attainment genetic variants as the potential instruments to evaluate the causal association between educational attainment and asthma using large-scale GWAS datasets of educational attainment (n = 405,072) and asthma (n = 30,810). We conducted a pleiotropy analysis using the MR-Egger intercept test and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. We performed an MR analysis using inverse-variance weighted, weighted median, MR-Egger, and MR-PRESSO. The main analysis method inverse-variance weighted indicated that each 1 standard deviation increase in educational attainment (3.6 years) could reduce 35% asthma risk [odds ratio (OR) = 0.65, 95% confidence interval (CI) 0.51–0.85, P = 0.001]. Importantly, evidence from other MR methods further supported this finding, including weighted median (OR = 0.55, 95% CI 0.38–0.80, P = 0.001), MR-Egger (OR = 0.48, 95% CI 0.16–1.46, P = 0.198), and MR-PRESSO (OR = 0.65, 95% CI 0.51–0.85, P = 0.0015). Meanwhile, we provide evidence to support that educational attainment protects against asthma risk dependently on cognitive performance using multivariable MR analysis. In summary, we highlight the protective role of educational attainment against asthma. Our findings may have public health applications and deserve further investigation.

Abstract 824: Germline genetic regulation of the adaptive immune response in colorectal cancer

Abstract Adaptive immune responses in the tumor microenvironment of colorectal cancer (CRC) play an important role in prognosis. However, the contributions of germline genetic variations to the strength and diversity of T cell responses in CRC are unclear. We conducted a genome-wide association study to examine the relationships between germline genetic variants and measures of the T cell repertoire in colorectal tumors. Germline DNA samples from 5,581 CRC cases recruited into the Molecular Epidemiology of Colorectal Cancer Study (MECC) were genotyped in batches using four different platforms. Genotype data were imputed to the Haplotype Reference Consortium panel separately by genotyping platform. Tumor DNA samples were extracted from paraffin blocks, and tumor infiltrating lymphocytes per high powered field (TILs/hpf) were quantified by a single gastrointestinal pathologist. TCR abundance and clonality within individual CRCs were measured using the immunoSEQ assay (Adaptive Biotechnologies). Appropriate quality control steps and data transformations were applied to fit downstream statistical modeling assumptions. After standard quality control on both imputed genotypes and transformed immune metrics, 2,876 (TILs/hpf) and 2,395 (TCR abundance and clonality) cases with approximately 9 million imputed genetic variants were included in the discovery phase. Logistic or linear regression models were used to evaluate the associations between allelic dosage of each variant and each immune-related outcome, adjusting for sex, age at diagnosis, genotyping platform, and principal components for global ancestry. Three independent datasets were available to replicate our findings using similar quality control measures and regression models: Colonomics (N=96; TILs/hpf, TCR abundance, clonality), the CRC Genetics Study (N=162; TCR abundance, clonality), and the Harvard Cohorts (N=505; TILs/hpf; in progress). The discovery phase identified 5 independent genetic variants associated with TILs/hpf, 15 associated with TCR abundance, and 19 associated with clonality at p&amp;lt;5X10E-06. Replication analyses as well as expression quantitative trait analyses and in silico functional annotation are underway for the loci of interest. Our study suggests that germline genetic variation is associated with the quantity and quality of adaptive immune responses in CRC. Citation Format: Stephanie L. Schmit, Ya-Yu Tsai, Joseph Bonner, Rebeca Sanz-Pamplona, Amit D. Joshi, Sidney S. Lindsey, Marilena Melas, Kevin J. McDonnell, Gregory E. Idos, Christopher P. Walker, W. Martin Kast, Diane Da Silva, Tomotaka Ugai, Hedy S. Rennert, Harlan S. Robins, Joel K. Greenson, Shuji Ogino, Victor Moreno, Gad Rennert, Stephen B. Gruber. Germline genetic regulation of the adaptive immune response in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 824.

Genetically predicted body composition in relation to cardiometabolic traits: a Mendelian randomization study.

Fat mass and fat-free mass are found to be associated with different health outcomes in observational studies, but the underlying causality remains unclear. We aimed to investigate the causal relationships between body composition and cardiometabolic traits using a two-sample Mendelian randomization (MR) approach. Independent genetic variants associated with body fat mass, fat-free mass, and fat percentage in UK Biobank population were used as genetic instrumental variables, and their causal effects on circulatory diseases, type 2 diabetes, glycemic traits, and lipid fractions were estimated from large-scale genome-wide association studies (GWAS) in European populations. Univariable, multivariable, and bidirectional MR analyses were performed. Genetically predicted high fat mass and fat percentage significantly increased risks of most cardiometabolic diseases, and high fat-free mass had protective effects on most cardiometabolic diseases after accounting for fat mass. Fat mass, fat-free mass, and fat percentage were all positively associated with higher risks of atrial fibrillation and flutter, varicose veins, and deep vein thrombosis and pulmonary embolism. High fat mass increased fasting glucose, homeostasis model assessment-insulin resistance (HOMA-IR), triglycerides, decreased high-density lipoprotein cholesterol, and high fat-free mass reduced HOMA-IR, triglycerides, and low-density lipoprotein cholesterol. Genetically predicted fat-free mass was bidirectionally negatively associated with 2-h glucose and total cholesterol. The findings may be helpful in risk stratification and tailoring management of body composition in patients with different cardiometabolic statuses.