Genome-wide Significance Level Research Articles

Sleep traits, fat accumulation, and glycemic traits in relation to gastroesophageal reflux disease: A Mendelian randomization study.

Sleep traits, fat accumulation, and glycemic traits are associated with gastroesophageal reflux disease (GERD) in observational studies. However, whether their associations are causal remains unknown. We performed a Mendelian randomization (MR) study to determine these causal relationships. Independent genetic variants associated with insomnia, sleep duration, short sleep duration, body fat percentage, visceral adipose tissue (VAT) mass, type 2 diabetes, fasting glucose, and fasting insulin at the genome-wide significance level were selected as instrumental variables. Summary-level data for GERD were derived from a genome-wide association meta-analysis including 78,707 cases and 288,734 controls of European descent. Inverse variance weighted (IVW) was used for the main analysis, with weighted median and MR-Egger as complements to IVW. Sensitivity analyses were performed using Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis to estimate the stability of the results. The MR study showed the causal relationships of genetically predicted insomnia (odds ratio [OR] = 1.306, 95% confidence interval [CI] 1.261 to 1.352; p = 2.24 × 10-51), short sleep duration (OR = 1.304, 95% CI: 1.147 to 1.483, p = 4.83 × 10-5), body fat percentage (OR = 1.793, 95% CI 1.496 to 2.149; p = 2.68 × 10-10), and visceral adipose tissue (OR = 2.090, 95% CI 1.963 to 2.225; p = 4.42 × 10-117) with the risk of GERD. There was little evidence for causal associations between genetically predicted glycemic traits and GERD. In multivariable analyses, genetically predicted VAT accumulation, insomnia, and decreased sleep duration were associated with an increased risk of GERD. This study suggests the possible roles of insomnia, short sleep, body fat percentage, and visceral adiposity in the development of GERD.

The genetic contribution of the X chromosome in age-related hearing loss.

Age-related (AR) hearing loss (HL) is the most common sensory impairment with heritability of 55%. The aim of this study was to identify genetic variants on chromosome X associated with ARHL through the analysis of data obtained from the UK Biobank. We performed association analysis between self-reported measures of HL and genotyped and imputed variants on chromosome X from ∼460,000 white Europeans. We identified three loci associated with ARHL with a genome-wide significance level (p < 5 × 10-8), ZNF185 (rs186256023, p = 4.9 × 10-10) and MAP7D2 (rs4370706, p = 2.3 × 10-8) in combined analysis of males and females, and LOC101928437 (rs138497700, p = 8.9 × 10-9) in the sex-stratified analysis of males. In-silico mRNA expression analysis showed MAP7D2 and ZNF185 are expressed in mice and adult human inner ear tissues, particularly in the inner hair cells. We estimated that only a small amount of variation of ARHL, 0.4%, is explained by variants on the X chromosome. This study suggests that although there are likely a few genes contributing to ARHL on the X chromosome, the role that the X chromosome plays in the etiology of ARHL may be limited.

Whole-Exome Sequencing Analyses Support a Role of Vitamin D Metabolism in Ischemic Stroke.

Ischemic stroke (IS) is a highly heritable trait, and genome-wide association studies have identified several commonly occurring susceptibility risk loci for this condition. However, there are limited data on the contribution of rare genetic variation to IS. We conducted an exome-wide study using whole-exome sequencing data from 152 058 UK Biobank participants, including 1777 IS cases. We performed single-variant analyses for rare variants and gene-based analyses for loss-of-function and deleterious missense rare variants. We validated these results through (1) gene-based testing using summary statistics from MEGASTROKE-a genome-wide association study of IS that included 67 162 IS cases and 454 450 controls, (2) gene-based testing using individual-level data from 1706 IS survivors, including 142 recurrent IS cases, enrolled in the VISP trial (Vitamin Intervention for Stroke Prevention); and (3) gene-based testing against neuroimaging phenotypes related to cerebrovascular disease using summary-level data from 42 310 UK Biobank participants with available magnetic resonance imaging data. In single-variant association analyses, none of the evaluated variants were associated with IS at genome-wide significance levels (P<5×10-8). In the gene-based analysis focused on loss-of-function and deleterious missense variants, rare genetic variation at CYP2R1 was significantly associated with IS risk (P=2.6×10-6), exceeding the Bonferroni-corrected threshold for 16 074 tests (P<3.1×10-6). Validations analyses indicated that CYP2R1 was associated with IS risk in MEGASTROKE (gene-based test, P=0.003), with IS recurrence in the VISP trial (gene-based test, P=0.001) and with neuroimaging traits (white matter hyperintensity, mean diffusivity, and fractional anisotropy) in the UK Biobank neuroimaging study (all gene-based tests, P<0.05). Because CYP2R1 plays an important role in vitamin D metabolism and existing observational evidence suggests an association between vitamin D levels and cerebrovascular disease, our results support a role of this pathway in the occurrence of IS.

Association between diverticular disease and colorectal cancer: a bidirectional mendelian randomization study

Background:Diverticular disease has been inconsistently associated with colorectal cancer risk. We conducted a bidirectional Mendelian randomization study to assess this association.Methods:Forty-three and seventy single-nucleotide polymorphisms associated with diverticular disease and colorectal cancer at the genome-wide significance level (p < 5 × 10− 8) were selected as instrumental variables from large-scale genome-wide association studies of European descent, respectively. Summary-level data for colon cancer, rectum cancer, and colorectal cancer were obtained from genome-wide association analyses of the FinnGen consortium and the UK Biobank study. Summary-level data for diverticular disease was derived from a genome-wide association study conducted in the UK Biobank population. The random effect inverse-variance weighted Mendelian randomization approach was used as the primary method and MR-Egger, weighted-median, and MR-PRESSO approaches were conducted as sensitivity analyses.Results:Genetically determined diverticular disease was associated with a higher risk of colorectal cancer (beta = 0.441, 95%CI: 0.081–0.801, P = 0.016) in the FinnGen population, but the association was not found in the UK Biobank (beta = 0.208, 95%CI: -0.291,0.532, P = 0.207). The positive association remained consistent direction in the three sensitivity analyses. In the stratified analysis in the FinnGen consortium, an association was found to exist between genetically predicted diverticular disease and colon cancer (beta = 0.489, 95%CI: 0.020–0.959, P = 0.041), rather than rectum cancer (beta = 0.328, 95%CI: -0.119-0.775, P = 0.151). Besides, we found a slight association between colorectal cancer and diverticular disease (beta = 0.007, 95%CI: 0.004–0.010, P < 0.001) when using colorectal cancer as exposome and diverticular disease as outcome. However, there is a large sample overlap in this step of analysis.Conclusion:This Mendelian randomization study suggests that diverticular disease may be a possible risk factor for colorectal cancer and colon cancer rather than rectum cancer in the FinnGen population.

Genetically predicted adipose tissue distribution influences the risk of atherosclerosis.

Truncal obesity is a key modifiable risk factor in cardiovascular disease (CVD). It is a highly complex phenotype, and numerous factors such as the distribution of adipose tissue may influence risk of CVD.1 However, while some studies have suggested that gluteofemoral fat deposits may serve a protective role, others have offered conflicting results.2,3 As observational studies may be vulnerable to confounding from environmental factors, we conducted a Mendelian randomization study investigating the effect of regional adipose tissue distribution on the risk of different types of atherosclerosis and heart failure (HF). The Mendelian randomization approach leverages genetic variation to infer causal associations as genetic variants in the human genome are inherited randomly, independently of environmental factors.4 All data used in this study were publicly available. First, we obtained summary statistics from a recent genome-wide association study on visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (AAT), and gluteofemoral adipose tissue (GFAT).5 Adipose tissue traits were determined by magnetic resonance imaging (MRI) of up to 39 076 individuals from the UK Biobank and were adjusted for age, sex, BMI, height, and 10 principal components. Instrument variables were selected from single-nucleotide polymorphisms (SNPs) that were robustly associated with the traits on a genome-wide significant level (P < 5 × 10−8). Instrument variables were pruned for linkage disequilibrium (LD), using a 10 megabase (Mb) window. For genetically correlated variants (R2 > 0.001), the variant with the smallest P-value was selected. We considered myocardial infarction (MI), large artery atherosclerotic stroke (LAS), and peripheral artery disease (PAD) as proxies for atherosclerosis. We acquired MI and LAS summary statistics from the CARDIoGRAMplusC4D consortium6 and the European subset of the GIGASTROKE consortium.7 Summary statistics for PAD and HF were obtained from the FinnGen study.8 There was no sample overlap between exposure and outcome datasets. For instrument variables not present in the outcome datasets, we identified suitable proxy SNPs in LD (r2 > 0.8).

Smoking, alcohol consumption, and 24 gastrointestinal diseases: Mendelian randomization analysis.

Whether the positive associations of smoking and alcohol consumption with gastrointestinal diseases are causal is uncertain. We conducted this Mendelian randomization (MR) to comprehensively examine associations of smoking and alcohol consumption with common gastrointestinal diseases. Genetic variants associated with smoking initiation and alcohol consumption at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank, FinnGen study, and other large consortia. Univariable and multivariable MR analyses were conducted to estimate the overall and independent MR associations after mutual adjustment for genetic liability to smoking and alcohol consumption. Genetic predisposition to smoking initiation was associated with increased risk of 20 of 24 gastrointestinal diseases, including 7 upper gastrointestinal diseases (gastroesophageal reflux, esophageal cancer, gastric ulcer, duodenal ulcer, acute gastritis, chronic gastritis, and gastric cancer), 4 lower gastrointestinal diseases (irritable bowel syndrome, diverticular disease, Crohn's disease, and ulcerative colitis), 8 hepatobiliary and pancreatic diseases (non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis, liver cancer, cholecystitis, cholelithiasis, and acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 20 associations persisted after adjusting for genetically predicted alcohol consumption. Genetically predicted higher alcohol consumption was associated with increased risk of duodenal ulcer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain statistically significant after adjustment for genetic predisposition to smoking initiation. This study provides MR evidence supporting causal associations of smoking with a broad range of gastrointestinal diseases, whereas alcohol consumption was associated with only a few gastrointestinal diseases. The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province; National Natural Science Foundation of China; Key Project of Research and Development Plan of Hunan Province; the Swedish Heart Lung Foundation; the Swedish Research Council; the Swedish Cancer Society.

Causal linkage of tobacco smoking with ageing: Mendelian randomization analysis towards telomere attrition and sarcopenia.

Ageing traits and frailty are important health issues in modern medicine. Evidence supporting the causal effects of tobacco smoking on various ageing traits is required. This study performed Mendelian randomization (MR) analysis instrumenting 377 genetic variants associated with being an ever-smoker at a genome-wide significance level to test the causal estimates from tobacco smoking. The outcome data were obtained from 337 138 white British ancestry participants from the UK Biobank. Leucocyte telomere length, appendicular lean mass index, subjective walking pace, handgrip strength,and wristband accelerometry-determined physical activity degree were collected as ageing-related outcomes. Summary-level MR analysis was performed using the inverse variance-weighted method and pleiotropy-robust MR methods, including weighted median and MR-Egger. Observational association between the outcome traits and phenotypically being an ever-smoker was also investigated. Summary-level MR analysis indicated that a higher genetic predisposition for tobacco smoking was significantly associated with shorter leucocyte telomere length (twofold increase in prevalence of smoking towards standardized Z-score, -0.041 [-0.054, -0.028]), lower appendicular lean mass index (-0.007 [-0.010, -0.005]), slower walking pace (ordinal category, -0.047 [-0.054, -0.033]) and lower time spent on moderate-to-vigorous physical activity (hours per week, -0.39 [-0.56, -0.23]). The causal estimates were non-significant towards handgrip strength phenotype (kg, 0.074 [-0.055, 0.204]). Pleiotropy-robust MR results generally supported the main causal estimates. The observational findings also showed significant association between being an ever-smoker and the ageing traits. Genetically predicted and observational tobacco smoking status are significantly associated with poor ageing phenotypes. Healthcare providers may continue to reduce tobacco use, which may be helpful in reducing the burden of ageing and frailty.

Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth

BackgroundRapid postnatal growth may result from exposure in utero or early life to adverse conditions and has been associated with diseases later in life and, in particular, with childhood obesity. DNA methylation, interfacing early-life exposures and subsequent diseases, is a possible mechanism underlying early-life programming.MethodsHere, a meta-analysis of Illumina HumanMethylation 450K/EPIC-array associations of cord blood DNA methylation at single CpG sites and CpG genomic regions with rapid weight growth at 1 year of age (defined with reference to WHO growth charts) was conducted in six European-based child cohorts (ALSPAC, ENVIRONAGE, Generation XXI, INMA, Piccolipiù, and RHEA, N = 2003). The association of gestational age acceleration (calculated using the Bohlin epigenetic clock) with rapid weight growth was also explored via meta-analysis. Follow-up analyses of identified DNA methylation signals included prediction of rapid weight growth, mediation of the effect of conventional risk factors on rapid weight growth, integration with transcriptomics and metabolomics, association with overweight in childhood (between 4 and 8 years), and comparison with previous findings.ResultsForty-seven CpGs were associated with rapid weight growth at suggestive p-value <1e−05 and, among them, three CpGs (cg14459032, cg25953130 annotated to ARID5B, and cg00049440 annotated to KLF9) passed the genome-wide significance level (p-value <1.25e−07). Sixteen differentially methylated regions (DMRs) were identified as associated with rapid weight growth at false discovery rate (FDR)-adjusted/Siddak p-values < 0.01. Gestational age acceleration was associated with decreasing risk of rapid weight growth (p-value = 9.75e−04). Identified DNA methylation signals slightly increased the prediction of rapid weight growth in addition to conventional risk factors. Among the identified signals, three CpGs partially mediated the effect of gestational age on rapid weight growth. Both CpGs (N=3) and DMRs (N=3) were associated with differential expression of transcripts (N=10 and 7, respectively), including long non-coding RNAs. An AURKC DMR was associated with childhood overweight. We observed enrichment of CpGs previously reported associated with birthweight.ConclusionsOur findings provide evidence of the association between cord blood DNA methylation and rapid weight growth and suggest links with prenatal exposures and association with childhood obesity providing opportunities for early prevention.

Appraising the Effects of Metabolic Traits on the Risk of Glaucoma: A Mendelian Randomization Study.

Metabolic traits are associated with the risk of developing glaucoma in observational studies. To assess whether theses associations reflect causality, we conducted a Mendelian randomization (MR) study. Our study included up to 20,906 glaucoma cases and 438,188 controls. Genetic instruments associated with the concerned 11 exposures at the genome-wide significance level were selected from corresponding genome-wide association studies. Summary-level data for glaucoma were obtained from the UK Biobank, the GERA study, and the FinnGen consortium. Univariable and multivariable MR analyses were conducted separately in two populations. Our results showed that higher genetic liability to type 2 diabetes (T2D) was causally and independently associated with an increased risk of glaucoma (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.06-1.16; p = 4.4 × 10-6). The association for T2D persisted after multivariable adjustment. In addition, higher genetically predicted systolic blood pressure (SBP), fasting glucose (FG), and HbA1c, were also suggestively associated with glaucoma risk. The OR was 1.08 (95% CI, 1.01-1.16; p = 0.035) for SBP, 1.24 (95% CI, 1.05-1.47; p = 0.011) for FG, and 1.28 (95% CI, 1.01-1.61; p = 0.039) for HbA1c. No evidence was observed to support the causal effects of body mass index and blood lipids for glaucoma. This study suggests a causal role for diabetes, as well as possible roles for higher SBP, FG, and HbA1c in the development of glaucoma. Further validation is needed to assess the potential of these risk factors as pharmacological targets for glaucoma prevention.

Causal relationship between moderate to vigorous physical activity and venous thromboembolism.

Previous studies have shown conflicting results about the impact of moderate to vigorous physical activity on the risk of venous thromboembolism (VTE). Using Mendelian randomization, we assessed whether moderate to vigorous physical activity causally affects VTE from genetic level. Genetic instruments associated with moderate to vigorous physical activity at the genome-wide significance level (P < 5×10- 8) were selected from the UK Biobank. Summary-level data for VTE were obtained from the FinnGen consortium. Univariable and multivariable Mendelian randomization analyses were conducted. Genetically predicted moderate to vigorous physical activity had no effect on VTE [odds ratio (OR) = 1.08; 95% confidence interval (CI) 0.66-1.78; P = 0.75] under a multiplicative random-effects inverse-variance weighted model. MR-Egger (OR = 0.20; 95% CI 0.01-4.70; P = 0.33), weighted median (OR = 1.08; 95% CI 0.52-2.25; P = 0.84), simple mode (OR = 2.53; 95% CI 0.59-10.92; P = 0.23), weighted mode (OR = 2.21; 95% CI 0.50-9.74; P = 0.31), and multivariable Mendelian randomization (OR = 0.74; 95% CI 0.46-1.19; P = 0.22) also yielded no significant association. The overall estimate was not influenced by individual single nucleotide polymorphism. No evidence of heterogeneity or horizontal pleiotropy was observed. Therefore, moderate to vigorous physical activity had no causal association with VTE in the general population.

Causal associations between erectile dysfunction and high blood pressure, negative psychology: a Mendelian randomization study

Erectile dysfunction (ED) has been closely associated with both high blood pressure (HBP) and psychological traits, but the causal relationship between them remains unclear. Herein, we aimed to identify the causal risk factors for ED. We conducted univariable and multivariable Mendelian randomization (MR) analyses using genetic variants associated with metabolic syndrome and psychology traits at the genome-wide significance (p &lt; 5 × 10−8) level obtained from corresponding genome-wide association studies. We used summary-level statistical data for ED from the European Bioinformatics Institute (EBI) database of complete Genome-Wide Association Studies (GWAS) summary data. We also conducted reverse causality and performed power calculations for MR. Our results showed that HBP was associated with increased odds of ED (odds ratio (OR) = 1.66 (95% confidence interval (CI), 1.13–2.45), a p-value for the inverse variance-weighted method (PIVW ) = 1.06 × 10−2, Power = 100%), as were myocardial infarction (OR = 1.09 (95% CI, 1.02–1.17), PIVW = 1.18 × 10−2, Power = 56%) and ischemic stroke (OR = 1.21 (95% CI, 1.02–1.43), PIVW = 2.87 × 10−2, Power = 10%). In terms of psychological traits, irritable mood (OR = 1.86 (95% CI, 1.14–3.02), PIVW = 1.30 × 10−2, Power = 96%) and neuroticism (OR = 1.36 (95% CI, 1.04–1.79), PIVW = 2.66 × 10−2, Power = 80%) were associated with increased odds of ED. Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) showed no evidence of pleiotropic bias, and sensitivity analyses confirmed the robustness of our results. We have established a causal link between HBP and ED, and we have also found evidence suggesting a causal relationship between irritable mood and ED.

Genome-wide analysis in the search for candidate genes associated with meat productivity traits in meat-and-dairy goats

The development of the tourism cluster in the North Caucasus causes the expansion of product range with high consumer characteristics, in particular, a sustainable offer of dairy and meat products labeled as environmentally friendly. In the range of such products with high dietary properties, a special role may be played by goat meat obtained from Karachay goats, which are the most common meat-and-dairy goats in the region. The aim of the work was to search for candidate genes associated with live weight and meat productivity of Karachay goats. GWAS analysis using Goat 50K BeadChip high-density DNA microarray determined a genome-wide level of significance for six SNPs located on chromosomes 5, 6, 10 and 16 associated with the live weight of young animals (4 and 8 months old). Three of the six SNPs within the ± 200 kb region were localized to HMGA2, CRADD, and MAX genes. These genes were selected to study the meat productivity traits of young goats with different genotypes. It was found that in the locus linked with HMGA2 gene, young goats with GG genotype were characterized by the best indicators of meat productivity. Compared to AA genotype animals, they had superiority in pre-slaughter weight, slaughter carcass weight, slaughter yield, boneless meat weight and loin eye area by 8.9%, 13.6%, 4.3% (P&lt;0.05), 10.5% (P&lt;0.05) respectively. Young goat meat of this genotype was characterized by the high protein content of 22.56% and low fat content of 9.12%. For the CRADD gene, animals with GG genotype had a higher pre-slaughter weight, slaughter weight, slaughter carcass yield, boneless meat weight and loin eye area. Animals with AG genotype were characterized by the lowest indicators. According to the above characteristics, the difference between the compared genotypes was 15.8%, 25.7% (P&lt;0.01), 8.4% (P &lt;0.05), 18.3%, and 15.7% (P 0.01) respectively. There were no significant differences in the chemical composition of muscle tissue between animals of different genotypes. HMGA2 and CRADD genes are promising for further research of Karachay goats breeding to increase meat productivity and meat quality.

Associations between serum urate and telomere length and inflammation markers: Evidence from UK Biobank cohort.

Hyperuricemia and gout have become gradually more common. The effect of serum urate on organism aging and systematic inflammation is not determined. This study aims to evaluate whether serum urate is causally associated with cellular aging markers and serum inflammation markers. A Mendelian randomization study was performed on summary-level data from the largest published genome-wide association studies. Single nucleotide polymorphisms with a genome-wide significance level were selected as instrumental variables for leukocyte telomere length (LTL), and serum soluble makers of inflammation (CRP, IL-6, TNF-α, and IGF-1). Standard inverse variance weighted (IVW) method was used as the primary statistical method. The weighted median, MR-Egger regression, and MR-PRESSO methods were used for sensitivity analysis. An inverse causal association of genetically predicted serum urate levels and LTL was found using IVW method (OR: 0.96, 95%CI 0.95, 0.97; β=-0.040; SE=0.0072; P=4.37×10-8). The association was also supported by MR results using MR-Egger method and weighted median method. The MR-PRESSO analysis and leave-one-out sensitivity analysis supported the robustness of the combined results. In terms of other aging-related serum biomarkers, there was no evidence supporting a causal effect of serum urate on CRP, IL-6, TNF-α, or IGF-1 levels. Serum urate levels are negatively associated with telomere length but are not associated with serum soluble indicators of inflammation. Telomere length may be a critical marker that reflects urate-related organismal aging and may be a mechanism in the age-related pathologies and mortality caused by hyperuricemia.

A genetic correlation and bivariate genome-wide association study of grip strength and depression.

Grip strength is an important biomarker reflecting muscle strength, and depression is a psychiatric disorder all over the world. Several studies found a significant inverse association between grip strength and depression, and there is also evidence for common physiological mechanisms between them. We used twin data from Qingdao, China to calculate genetic correlations, and we performed a bivariate GWAS to explore potential SNPs, genes, and pathways in common between grip strength and depression. 139 pairs of Dizygotic twins were used for bivariate GWAS. VEAGSE2 and PASCAL software were used for gene-based analysis and pathway enrichment analysis, respectively. And the resulting SNPs were subjected to eQTL analysis and pleiotropy analysis. The genetic correlation coefficient between grip strength and depression was -0.41 (-0.96, -0.15). In SNP-based analysis, 7 SNPs exceeded the genome-wide significance level (P<5×10-8) and a total of 336 SNPs reached the level of suggestive significance (P<1×10-5). Gene-based analysis and pathway-based analysis identified genes and pathways related to muscle strength and the nervous system. The results of eQTL analysis were mainly enriched in tissues such as the brain, thyroid, and skeletal muscle. Pleiotropy analysis shows that 9 of the 15 top SNPs were associated with both grip strength and depression. In conclusion, this bivariate GWAS identified potentially common pleiotropic SNPs, genes, and pathways in grip strength and depression.

Metabolically favorable adiposity and bone mineral density: a Mendelian randomization analysis.

This analysis assessed the putative causal association between genetically predicted percent body fat and areal bone mineral density (aBMD)and, more specifically, the association between genetically predicted metabolically "favorable adiposity" (MFA) and aBMD at clinically relevant bone sites. Mendelian randomization was used to assess the relationship of MFA and percent body fat with whole-body, lumbar spine, femoral neck, and forearm aBMD. Sex-stratified and age-stratified exploratory analyses were conducted. In all MR analyses, genetically predicted MFA was inversely associated with aBMD for the whole body (β=-0.053, p=0.0002), lumbar spine (β=-0.075; p=0.0001), femoral neck (β=-0.045; p=0.008), and forearm (β=-0.115; p=0.001). This negative relationship was strongest in older individuals and did not differ by sex. The relationship between genetically predicted percent body fat and aBMD was nonsignificant across all Mendelian randomization analyses. Several loci that were associated at a genome-wide significance level (p < 5 × 10-8 ) in opposite directions with body fat and aBMD measures were also identified. This study did not support the hypothesis that MFA protects against low aBMD. Instead, it showed that MFA may result in lower aBMD. Further research is needed to understand how MFA affects aBMD and other components of bone health such as bone turnover, bone architecture, and osteoporotic fractures.

Genetically Proxied Angiotensin‐Converting‐Enzyme Inhibition is Potentially Causal for Alzheimer Disease: A Mendelian Randomization Study

AbstractBackgroundAngiotensin‐converting enzyme (ACE) has been implicated in the pathogenesis of Alzheimer disease (AD), in which ACE plays a role in metabolizing Amyloid Beta (AB). Genetic variants in the ACE locus have also been associated with AD. The effect of ACE inhibitors on AD risk remains unclear. We sought to investigate the potential causal relationship between ACE inhibition and AD and other neurodegenerative disorders using a mendelian randomization (MR) approach.MethodA genetic proxy for ACE inhibition (MR exposure) was generated using 17 single nucleotide polymorphisms (SNPs) in the ACE gene that were previously associated with lower ACE blood levels in a candidate gene study (n = 4,147; adjusted‐P &lt; 0.05). Summary genome‐wide association study (GWAS) statistics for AD (111,326 cases, 677,663 controls), Frontotemporal dementia (FTD) (3526 cases, 9402 controls) and Lewy body dementia (LBD) (cases 2591, controls 4027) were used as proxies for the MR outcomes. Inverse weighted variance MR was performed to test the potentially causal relationship between the exposure and outcomes. Sensitivity analyses were completed to test the robustness of the results.ResultACE inhibition was significantly associated with increased risk of AD (OR = 1.07, P = 0.0000005); with robust and consistent effects in all sensitivity analyses. Using leave one out method; rs4343 (A allele) showed the strongest effect. rs4343 is in mild linkage disequilibrium with the SNP associated at genome wide significant level with AD rs4277405 (R2 0.35). Rerunning the MR analysis on the AD cohort after removing rs4343 continued to show significant results (OR = 1.04, P = 0.02). ACE inhibition was also associated with increased risk for FTD (OR = 1.16, P = 0.009), but the findings were not robust in some sensitivity analyses, possibly due to lower sample size of FTD cohort. ACE inhibition was not associated with LBD.ConclusionThis is the first study to provide robust genetic evidence for the potentially causal relationship between ACE inhibition in the blood and the diagnosis of AD. These results should encourage further investigation of the potential neurodegenerative side effects of ACE inhibition; and further suggest ACE related pathways as pharmacological targets for treatment and/or prevention of AD.

Novel Genetic Determinants of Dental Maturation in Children

Dental occlusion requires harmonious development of teeth, jaws, and other elements of the craniofacial complex, which are regulated by environmental and genetic factors. We performed the first genome-wide association study (GWAS) on dental development (DD) using the Demirjian radiographic method. Radiographic assessments from participants of the Generation R Study (primary study population, N1 = 2,793; mean age of 9.8 y) were correlated with ~30 million genetic variants while adjusting for age, sex, and genomic principal components (proxy for population stratification). Variants associated with DD at genome-wide significant level (P < 5 × 10−8) mapped to 16q12.2 (IRX5) (lead variant rs3922616, B = 0.16; P = 2.2 × 10−8). We used Fisher’s combined probability tests weighted by sample size to perform a meta-analysis (N = 14,805) combining radiographic DD at a mean age of 9.8 y from Generation R with data from a previous GWAS (N2 = 12,012) on number of teeth (NT) in infants used as proxy of DD at a mean age of 9.8 y (including the ALSPAC and NFBC1966). This GWAS meta-analysis revealed 3 novel loci mapping to 7p15.3 (IGF2BP3: P = 3.2 × 10−8), 14q13.3 (PAX9: P = 1.9 × 10−8), and 16q12.2 (IRX5: P = 1.2 × 10−9) and validated 8 previously reported NT loci. A polygenic allele score constructed from these 11 loci was associated with radiographic DD in an independent Generation R set of children (N = 703; B = 0.05, P = 0.004). Furthermore, profiling of the identified genes across an atlas of murine and human stem cells observed expression in the cells involved in the formation of bone and/or dental tissues (>0.3 frequency per kilobase of transcript per million mapped reads), likely reflecting functional specialization. Our findings provide biological insight into the polygenic architecture of the pediatric dental maturation process.

Causal effects of B vitamins and homocysteine on obesity and musculoskeletal diseases: A Mendelian randomization study.

Although homocysteine (Hcy) increases the risk of cardiovascular diseases, its effects on obesity and musculoskeletal diseases remain unclear. We performed a Mendelian randomization study to estimate the associations between Hcy and B vitamin concentrations and their effects on obesity and musculoskeletal-relevant diseases in the general population. We selected independent single nucleotide polymorphisms of Hcy (n = 44,147), vitamin B12 (n = 45,576), vitamin B6 (n = 1864), and folate (n = 37,465) at the genome-wide significance level as instruments and applied them to the studies of summary-level data for fat and musculoskeletal phenotypes from the UK Biobank study (n = 331,117), the FinnGen consortium (n = 218,792), and other consortia. Two-sample Mendelian randomization (MR) approaches were utilized in this study. The inverse variance weighting (IVW) was adopted as the main analysis. MR-PRESSO, MR-Egger, the weighted median estimate, bidirectional MR, and multivariable MR were performed as sensitivity methods. Higher Hcy concentrations were robustly associated with an increased risk of knee osteoarthritis [odds ratio (OR) 1.119; 95% confidence interval (CI) 1.032-1.214; P = 0.007], hospital-diagnosed osteoarthritis (OR 1.178; 95% CI 1.012-1.37; P = 0.034), osteoporosis with pathological fracture (OR 1.597; 95% CI 1.036-2.46; P = 0.034), and soft tissue disorder (OR 1.069; 95% CI 1.001-1.141; P = 0.045) via an inverse variance weighting method and other MR approaches. Higher vitamin B12 levels were robustly associated with decreased body fat percentage and its subtypes (all P < 0.05). Bidirectional analyses showed no reverse causation. Multivariable MR analyses and other sensitivity analyses showed directionally similar results. There exist significant causal effects of vitamin B12 in the serum and Hcy in the blood on fat and musculoskeletal diseases, respectively. These findings may have an important insight into the pathogenesis of obesity and musculoskeletal diseases and other possible future therapies.

Age at menarche and ischemic heart disease: An update mendelian randomization study.

Background: Although earlier menarche age has been associated with ischemic heart disease in previous observational studies, the relationship's causation has not been shown. Through two-sample Mendelian randomization (MR), we were able to define the causal connection. Methods: We performed Mendelian Randomization (MR) analysis to explore the associations between genetically predicted AAM and IHD. Summary-level databases for exposure and outcome were selected from the MR-Base database (https://gwas.mrcieu.ac.uk/). Single-nucleotide polymorphisms (SNPs) connected to AAM at genome-wide significance level (p < 5 × 10-8) were considered as instrumental variables (IVs). We used four methods to pool MR estimates, including fixed-effects inverse variance weighting (fe-IVW), multiplicative random-effects inverse variance weighting (mre-IVW), weighted median (WM), and MR-Egger regression methods. Sensitivity analyses were performed to evaluate the robustness of the results. PhenoScanner searches and Multivariable Mendelian randomization (MVMR) analysis was used for assessing confounders. Results: 117 SNPs significantly correlated with AAM were screened as instruments, the results of three main methods showed that genetically earlier AAM may have a causal effect on the higher risk of IHD (fe-IVW: OR = 0.80, 95% CI: 0.72-0.88, p < 0.001; mre-IVW: OR = 0.80, 95% CI: 0.70-0.90, p < 0.001; WE: OR = 0.79, 95% CI: 0.66-0.93, p = 0.006). These results were consistent across sensitivity analyses. MR analysis revealed that there was still a relationship between AAM and IHD even when pleiotropic SNPs of confounders were removed employing PhenoScanner searches. In MVMR, the significant association remained after adjusting for biological sex, but it was attenuated with adjustment of body mass index including childhood and adult. Conclusion: Our MR analysis revealed a substantial genetically determined confounder-mediated relationship between an increase in genetically predicted AAM and a lower risk of IHD. By addressing the intervention of body mass index, the risk of IHD may be lowered.

Bidirectional Association between Major Depressive Disorder and Gastroesophageal Reflux Disease: Mendelian Randomization Study.

Observational research has found a bidirectional relationship between major depressive disorder and gastroesophageal reflux disease; however, the causal association of this relationship is undetermined. A bidirectional Mendelian randomization study was performed to explore the causal relationships between major depressive disorder and gastroesophageal reflux disease. For the instrumental variables of major depressive disorder and gastroesophageal reflux disease, 31 and 24 single-nucleotide polymorphisms without linkage disequilibrium (r2 ≤ 0.001) were selected from relevant genome-wide association studies, respectively, at the genome-wide significance level (p ≤ 5 × 10-8). We sorted summary-level genetic data for major depressive disorder, gastroesophageal reflux disease, gastroesophageal reflux disease without esophagitis, and reflux esophagitis from meta-analysis study of genome-wide association studies involving 173,005 individuals (59,851 cases and 113,154 non-cases), 385,276 individuals (80,265 cases and 305,011 non-cases), 463,010 individuals (4360 cases and 458,650 non-cases), and 383,916 individuals (12,567 cases and 371,349 non-cases), respectively. Genetic liability to major depressive disorder was positively associated with gastroesophageal reflux disease and its subtypes. Per one-unit increase in log-transformed odds ratio of major depressive disorder, the odds ratio was 1.31 (95% confidence interval [CI], 1.19-1.43; p = 1.64 × 10-8) for gastroesophageal reflux disease, 1.51 (95% CI, 1.15-1.98; p = 0.003) for gastroesophageal reflux disease without esophagitis, and 1.21 (95% CI, 1.05-1.40; p = 0.010) for reflux esophagitis. Reverse-direction analysis suggested that genetic liability to gastroesophageal reflux disease was causally related to increasing risk of major depressive disorder. Per one-unit increase in log-transformed odds ratio of gastroesophageal reflux disease, the odds ratio of major depressive disorder was 1.28 (95% confidence interval, 1.11-1.47; p = 1.0 × 10-3). This Mendelian randomization study suggests a bidirectional causal relationship between major depressive disorder and gastroesophageal reflux disease.