Independent Single Nucleotide Polymorphisms Research Articles

The Association between Blood Lipids and Systemic Lupus Erythematosus: A Two-Sample Mendelian Randomization Research.

We evaluated the causal effects of blood lipid levels on systemic lupus erythematosus with a two-sample Mendelian randomization analysis. Independent single-nucleotide polymorphisms related to blood lipids levels (p < 5 × 10-8) were selected as instrumental variables (IVs) from a published genome-wide association study (GWAS). SLE GWAS analysis that included 4036 cases and 6959 controls of European ancestry provided the related roles between instrumental variables and result (SLE). The causal effects were evaluated with two-sample Mendelian randomization (MR) analyses. According to the inverse-variance weighted approaches, genes predictive of increased LDL cholesterol (OR: 1.131; 95% CI: 0.838, 1.528; p = 0.420), HDL cholesterol (OR: 1.093; 95% CI: 0.884, 1.352; p = 0.412), triglycerides (OR: 0.903; 95% CI: 0.716, 1.137; p = 0.384), Apolipoprotein A-I (OR: 0.854; 95% CI: 0.680, 1.074; p = 0.177), and Apolipoprotein B (OR: 0.933; 95% CI: 0.719, 1.211; p = 0.605) were not causally related to the risk of SLE, consistent with multivariate Mendelian randomization analysis. The reverse-MR analyses showed no massive causal roles between SLE and LDL cholesterol (OR: 0.998; 95% CI: 0.994, 1.001; p = 0.166) as well as Apolipoprotein B (OR: 0.998; 95% CI: 0.994, 1.001; p = 0.229). Nevertheless, a causal role of SLE in decreasing HDL cholesterol (OR: 0.993; 95% CI: 0.988, 0.997; p = 0.002), triglycerides (OR: 0.996; 95% CI: 0.993, 0.999; p = 0.010), and Apolipoprotein A-I (OR: 0.995; 95% CI: 0.990, 0.999; p = 0.026) was validated to some extent. Our study found no causal association between abnormal blood lipids and SLE nor a causal effect between SLE and LDL cholesterol as well as Apolipoprotein B. Nevertheless, some evidence showed that SLE exerted a causal effect on lowering HDL cholesterol, Apolipoprotein A-I, and triglyceride levels.

Body surface area is a potential obesity index: Its genetic determination and its causality for later-life diseases.

This study aimedto identify novel genetic factors that contribute to body surface area (BSA) and explore its relationship with complex traits and diseases. Based on more than 330,000 European individuals in the UK Biobank, the first large-scale genome-wide association study for BSA was performed. Comprehensive genetic analysis and enrichment analysis were then performed to explore the biological function of the identified loci. The genetic correlations and causal associations between BSA and other anthropometry parameters, early growth indices, and later-life diseases, respectively, were assessed by complex genetic approaches. Genome-wide association study analysis identified a total of 456 conditionally independent single-nucleotide polymorphism mapping genes with known functions in the regulation of adipogenesis and metabolism and enriched in adipogenesis-related pathways. BSA was highly genetically correlated with obesity phenotypes, and all the studied anthropometry parameters from the UK Biobank were significantly positively associated with BSA. BSA was phenotypically associated with 13 chronic diseases and genetically associated with 6 diseases. Mendelian randomization analyses showed that BSA has a causal effect in increasing the risk of some diseases. These findings increase understanding of genetic determinants for BSA and its relationship with complex traits and diseases, and BSA could be regarded as a potential obesity trait.

Causal associations between gastroesophageal reflux disease and lung cancer risk: A Mendelian randomization study.

Observational epidemiological studies suggest that lung cancer risk may be raised by gastroesophageal reflux disease (GERD); however, the causal relationship between them remains unknown. Our study performed the two-sample Mendelian randomization (MR) approach to examine the causal relationship between GERD and lung cancer. Instrument variables were found to be independent single nucleotide polymorphisms (SNPs) that were highly linked with GERD (n=129,080). Summary data from genome-wide association studies (GWAS) data were used to determine outcomes for lung cancer (n=11,348), squamous cell lung cancer (LUSC), and lung adenocarcinoma (LUAD). In this study, three MR statistical techniques (inverse variance weighted (IVW), MR-Egger, and weighted median) were used to examine the potential causative relationship between GERD and the risk of lung cancer. Cochran's Q test, MR-Egger intercept test, leave-one-out analysis, and the funnel plot were all used in sensitivity analyses. The main IVW method revealed that GERD substantially increased the risk of lung cancer [odds ratio (OR)=1.37; 95% CI 1.16-1.63, p=0. 0003], which was also supported by weighted median and MR-Egger analyses. Using IVW estimate, similar causal relationships were also observed between GERD and LUSC (OR=1.56; 95% CI 1.26-1.93, p=5.35 × 10-5 ) and LUAD (OR=1.45; 95% CI 1.09-1.93, p=0.01). Although potential heterogeneity was observed in some studies, random effect IVW was not violated by the heterogeneity, indicating that the causal effect was robust. GERD was positively associated with the risk of lung cancer, for LUSC and LUAD. This study shed light on a new direction for prevent strategy of lung cancer and therapeutic perspectives in patients with GERD.

Homocysteine, folate, and nonalcoholic fatty liver disease: a systematic review with meta-analysis and Mendelian randomization investigation

Circulating concentrations of homocysteine and folate are inconsistently associated with the risk of nonalcoholic fatty liver disease (NAFLD) in observational studies. We conducted a meta-analysis and Mendelian randomization (MR) analyses to examine these associations. We performed a meta-analysis of observational studies identified from 3 databases to evaluate the associations of serum homocysteine and folate concentrations with NAFLD from inception to 7 April 2022. We conducted MR analyses to strengthen the causal inference in these associations. Independent single-nucleotide polymorphisms without linkage disequilibrium (r2<0.01) that were strongly associated (P < 5×10-8) with serum homocysteine (n=13) and folate (n=2) concentrations were selected as instrumental variables from 2 meta-analyses of genome-wide association studies (GWASs) of 44,147 and 37,645 individuals of European ancestry, respectively. Data on NAFLD were obtained from a GWAS of 8434 NAFLD cases and 770,180 controls of European ancestry. We further included 4 liver enzymes as secondary outcomes from a GWAS of 361,194 individuals with European descent. Twenty-two observational studies comprising 30,368 participants were included in the meta-analysis. There was a positive association between serum homocysteine and NAFLD risk (n=20; OR: 1.96; 95% CI: 1.57, 2.45) and an inverse association between serum folate and NAFLD risk (n=12; OR: 0.75; 95% CI: 0.58, 0.99). In MR analysis, the ORs of NAFLD were 1.17 (95% CI: 1.01, 1.36) and 0.75 (95% CI: 0.55, 1.02) per 1-SD increment of genetically predicted circulating concentrations of homocysteine and folate, respectively. Each 1-SD increase of genetically predicted circulating homocysteine and folate conferred a change in ALT concentrations of 0.62 U/L (95% CI: 0.20, 1.04) and -0.84 U/L (95% CI: -0.14, -1.54). This study suggests a potential role of circulating homocysteine and possibly folate in NAFLD, which calls for future clinical exploration of the possibility of lowering homocysteine concentrations to prevent NAFLD. This systematic review was registered at PROSPERO as CRD42021296434.

Relationship between alcohol consumption and dementia with Mendelian randomization approaches among older adults in the United States

AbstractBackgroundPrior research is mixed concerning the association between alcohol consumption, a modifiable factor, and dementia. Genetic causal inference approaches may help elucidate the relationship between alcohol consumption and dementia.MethodWe performed a two‐sample Mendelian randomization study using harmonized, genome‐wide significant (p‐value&lt;10−8), and independent (r2&lt;.001) single nucleotide polymorphisms’ (SNPs) summary statistics from the largest publicly available meta‐analyses of genome‐wide association studies of weekly alcohol consumption (Liu et al., 2019, n = 941,280) and late onset Alzheimer’s disease (Kunkle et al., 2019, n = 21,982 cases, 41,944 controls). Next, in the 2012 wave of the United States Health and Retirement Study (HRS), we employed individual polygenic scores of alcohol consumption via one‐sample Mendelian randomization. Polygenic scores were calculated and standardized within genetic ancestry across 1,399,824 SNPs overlapping Liu et al. without HRS and 23andMe samples (n = 522,159). G‐estimation provided odds ratios (ORs) of the relationship between a standard deviation increase in genetic risk of alcohol consumption and dementia and cognitive impairment without dementia compared to normal cognition in models stratified by genetic ancestry.ResultOf 99 SNPs associated with weekly alcoholic drink consumption and 71 SNPs associated with late onset Alzheimer’s disease, 59 overlapping and harmonized SNPs met instrument selection criteria. We did not observe evidence of a relationship between alcohol consumption and late‐onset Alzheimer’s disease using the inverse variance weighted two‐sample Mendelian randomization estimator (OR = 1.15, 95% confidence interval (CI):[0.78, 1.72]), nor with complementary estimators. In HRS, Mendelian randomization revealed no relationship between cumulative genetic alcohol consumption risk and cognitive impairment without dementia (African ancestry sample (n = 2,402, OR = 0.86, 95% CI:[0.47, 1.58]); European ancestry sample (n = 9,576, OR = 0.96, 95% CI:[0.86, 1.07])) and dementia in the African ancestry sample (n = 1,908, OR = 0.50, 95% CI:[0.13, 2.00]). Alcohol consumption genetic risk was inversely associated with dementia in the European ancestry sample (n = 8,518, OR = 0.77, 95% CI:[0.62, 0.95]).ConclusionOur results largely suggest there is no causal relationship between alcohol consumption and dementia. The protective association observed between alcohol consumption and dementia among those of European ancestry in an aging American cohort may be due to genetic pleiotropy and/or selection bias in our empirical sample within the Health and Retirement Study.

Brain Structure and Allelic Associations in Alzheimer’s Disease

AbstractBackgroundThis paper examines late‐onset dementia‐related cognitive impairment utilizing neuroimaging‐genetics biomarker associations.MethodThe participants, ages 65 to 85, included 266 normal controls (CN’s), 572 mild cognitive impairment (MCI’s), and 188 Alzheimer’s disease (AD) patients. Genotype dosage data for AD‐associated single nucleotide polymorphisms (SNPs) were extracted from the imputed ADNI genetics dosage data using sample‐major additive coding. 29 such SNPs were selected, representing a subset of independent SNPs reported to be highly associated with AD in a recent AD meta‐GWAS study by Jansen et al.ResultThe expected significant correlations between the SNPs and the neuroimaging phenotypes were confirmed using the top 29 genomic markers (GMs) and 200 neuroimaging markers (NIMs). Relative to CN, odds ratios and relative risks for AD and MCI were employed for prediction using multinominal linear modeling of diagnosis. In the CN and MCI cohorts, mainly cortical thickness measures were associated with GMs among thickness and the other measures, even though it was not in the AD cohort. Network patterns within the CN and AD groups were shown as separated 3 group metrics including thickness, volume, and pct (the proportion of White to Gray Matter), but not in the MCI cohort. Multinominal linear model of clinical diagnosis showed precisely the specific NIMs and GMs that were most impactful in discriminating between AD and CN and between MCI and CN.ConclusionAdvanced analytics provide mechanisms for exploring the interrelations between morphometric biomarkers and genomic indicators. This facilitates clinical investigation of phenotypic associations and facilitates deep systematic understanding of AD pathogenesis.

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.

Causal effects of homocysteine levels on the components of sarcopenia: A two-sample mendelian randomization study.

Background: Currently, it is unclear whether there is a causal association between genetically predicted plasma homocysteine (Hcy) levels and the risk of sarcopenia. We performed a Mendelian randomization (MR) study to assess the association between circulating Hcy levels and the components [grip strength, walking pace, and appendicular lean mass (ALM)] of sarcopenia. Methods: Independent single nucleotide polymorphisms (SNPs) significantly associated with plasma Hcy levels served as instrumental variables. Summary-level data regarding the components of sarcopenia. Were obtained from the UK Biobank. Inverse variance weighted (IVW) as the primary method was used for Mendelian randomization (MR) analysis. We also use four models, weighted median, MR-Egger regression, Maximum likelihood, and Penalised weighted median, as supplementary methods to IVW. The MR-Egger intercept test, Cochran's Q test, and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of the causal association between Hcy levels and the components of sarcopenia. Results: The IVW-MR analysis suggested significant negative associations of increased plasma Hcy levels with grip strength (right: effect = -0.036, SE = 0.032, p = 5.53E-4; left: effect = -0.045, SE = 0.010, p = 1.45E-5), walking pace (effect = -0.038, SE = 0.011, p = 3.18E-4), and ALM (effect = -0.058, 0.013, p = 1.03E-5). However, there were no significant associations of decreased plasma Hcy levels with grip strength (right: effect = 0.005, SE = 0.021, p = 0.82; left: effect = -0.006, SE = 0.014, p = 0.64), walking pace (effect = 0.01, 0.020, p = 0.61), or ALM (effect = -0.034, SE = 0.018, p = 0.06).The accuracy and robustness of these findings were confirmed by sensitivity tests. Conclusion: Increased circulating Hcy levels were associated with lower grip strength, slower walking pace, and decreased ALM.

Transcriptome-based analyses of adaptive divergence between two closely related spruce species on the Qinghai-Tibet plateau and adjacent regions.

Speciation among populations connected by gene flow is driven by adaptation to different environments, but underlying gene-environment associations remain largely unknown. Here, 162 individuals from 32 populations were sampled to obtain 191,648 independent single nucleotide polymorphisms (SNPs) across the genomes of two closely related spruce species, Picea asperata and Picea crassifolia, which occur on the Qinghai-Tibet Plateau and in surrounding regions. Using the SNP data set, genotype-environment associations and demographic modelling were used to examine local adaptation and genetic divergence between these two species. While morphologically similar, the two Picea species were genetically differentiated in multiple analyses. These species diverged despite continuous gene flow, and their initial divergence was dated back to the late Quaternary. The effective population sizes of both species have expanded since their divergence, as confirmed by niche distribution simulations. A total of 6365 genes were associated with the tested environmental variables; of these, 41 were positively selected in P. asperata and were mainly associated with temperature, while 83 were positively selected in P. crassifolia and were primarily associated with precipitation. These results deepen our understanding of the adaptive divergence and demographic histories of these two spruce species and highlight the importance of genomic data in deciphering the environmental selection underlying Quaternary interspecific divergence.

Abstract 11540: Dephospho-Uncarboxylated Matrix Gla-Protein and Adverse Outcomes in Heart Failure: A Mendelian Randomization Analysis

Introduction: Matrix Gla-protein (MGP) is a known inhibitor of vascular calcification and is activated by vitamin K-dependent carboxylation. Carboxylation is reduced in vitamin K-deficient states, resulting in increased circulating dephospho-uncarboxylated MGP (dpucMGP). Elevated dpucMGP levels have been associated with large artery stiffenning and worse outcomes in heart failure (HF). We assessed the causal relationship between dpucMGP and adverse outcomes in human HF using Mendelian Randomization (MR). Methods: We measured dpucMGP among 2379 Penn Heart Failure Study (PHFS) participants and analyzed a subset with genotypic data (n=1334). We constructed a genetic risk score (GRS) using independent single nucleotide polymorphisms (SNPs) associated with dpucMGP levels at genome-wide significance, and utilized MR analysis to assess the association between genetically determined dpucMGP levels and 1) all-cause death, and 2) death or heart failure-related hospital admission (DHFA). Results: Measured dpucMGP levels were associated with an increased risk of death ( Figure 1A ) and DHFA ( Figure 1B ). DpucMGP levels were significantly associated with 55 genome-wide SNPs. MR analysis demonstrated a significant relationship between genetically determined dpucMGP and the risk of death (hazard ratio [HR] 1.67, P =0.013) and DHFA (HR 1.51, P =0.004). Conclusions: Elevated dpucMGP levels are associated with increased risk for all-cause death and DHFA in patients with heart failure, and this relationship is likely causal. Further studies are required to determine the role of vitamin K supplementation in this patient population.

Abstract 12228: Development of a Novel Polygenic Risk Score to Predict Risk of Aortic Stenosis Events

Introduction: Aortic stenosis (AS) is the most common valvular heart disease. Polygenic risk scores (PRS) use common genetic variants to enhance risk prediction for disease but have not yet been applied in AS. Methods: We generated an AS genetic risk score using summary data from a recently performed GWAS in the Million Veteran Program and score selection performed in the UK Biobank. We analyzed investigator reported adverse events with either newly identified AS or worsening of AS (including heart failure in the setting of AS or aortic valve replacement) from 5 TIMI trials (FOURIER, PEGASUS, SAVOR, SOLID, and ENGAGE). Cox proportional hazard models (adjusted for age, sex, diabetes, BMI, hyperlipidemia, and the first 5 principal components) were used to generate adjusted hazard ratios for risk of AS evaluating normalized PRS as a continuous variable. Results: The best performing AS PRS used a p-value threshold of 5x10 -8 and consisted of 27 independent single nucleotide polymorphisms which together predicted AS in the UKBB with a p-value of 2.6x10 -5 . In the TIMI trials, there were a total of 52,183 individuals (median age 66 years [interquartile range 60-72], 71.7% male) with a median follow up of 2.4 years. Of these, 215 (0.4%) had an AS-related adverse event. Age was the strongest clinical risk factor for an AS-related adverse event (HR 1.08 [1.06-1.10] per 1-SD, p-value 1.8x10 -19 ), followed by diabetes and BMI. After adjustment for all clinical risk factors there was a 16% increase in the risk of an AS-related adverse event with each standard deviation (SD) increase in the AS PRS (HR 1.16 [1.02-1.31] per 1-SD, p-value 0.03). Conclusions: We developed a novel polygenic risk score that predicts clinical risk of aortic stenosis-related adverse events in patients with cardiometabolic disease, even after adjustment for traditional risk factors.

Plasma phospholipid arachidonic acid in relation to non-alcoholic fatty liver disease: Mendelian randomization study

ObjectivesThe role of plasma phospholipid arachidonic acid (AA) in the development of non-alcoholic fatty liver disease (NALFD), cirrhosis, and liver cancer remains unclear. This study aimed to determine the causality of the associations of plasma phospholipid AA with NALFD, cirrhosis, and liver cancer using Mendelian randomization analysis. MethodsNine independent single-nucleotide polymorphisms associated with plasma phospholipid AA at the genome-wide significance were used as instrumental variables. Summary-level data for three outcomes were obtained from 1) a genome-wide association study for NAFLD, 2) the UK Biobank study, and 3) the FinnGen study. The sensitivity analysis excluding the pleiotropic variant rs174547 in the FADS1 gene was performed. Estimates from different sources were combined using the fixed-effects meta-analysis method. ResultsPer standard deviation increase in AA levels, the combined odds ratio was 1.06 (95% confidence interval, 1.02–1.11; P = 0.008) for NAFLD, 1.05 (95% confidence interval, 1.01–1.09; P = 0.009) for cirrhosis, and 0.99 (95% confidence interval, 0.94–1.05; P = 0.765) for liver cancer. The associations remained stable in the sensitivity analysis excluding rs174547. ConclusionsThis study suggests potential causal associations of high levels of plasma phospholipid AA with the risk of NAFLD and cirrhosis.

Genome-Wide Association Analysis of Over 170,000 Individuals from the UK Biobank Identifies Seven Loci Associated with Dietary Approaches to Stop Hypertension (DASH) Diet.

Diet is a modifiable risk factor for common chronic diseases and mental health disorders, and its effects are under partial genetic control. To estimate the impact of diet on individual health, most epidemiological and genetic studies have focused on individual aspects of dietary intake. However, analysing individual food groups in isolation does not capture the complexity of the whole diet pattern. Dietary indices enable a holistic estimation of diet and account for the intercorrelations between food and nutrients. In this study we performed the first ever genome-wide association study (GWA) including 173,701 individuals from the UK Biobank to identify genetic variants associated with the Dietary Approaches to Stop Hypertension (DASH) diet. DASH was calculated using the 24 h-recall questionnaire collected by UK Biobank. The GWA was performed using a linear mixed model implemented in BOLT-LMM. We identified seven independent single-nucleotide polymorphisms (SNPs) associated with DASH. Significant genetic correlations were observed between DASH and several educational traits with a significant enrichment for genes involved in the AMP-dependent protein kinase (AMPK) activation that controls the appetite by regulating the signalling in the hypothalamus. The colocalization analysis implicates genes involved in body mass index (BMI)/obesity and neuroticism (ARPP21, RP11-62H7.2, MFHAS1, RHEBL1). The Mendelian randomisation analysis suggested that increased DASH score, which reflect a healthy diet style, is causal of lower glucose, and insulin levels. These findings further our knowledge of the pathways underlying the relationship between diet and health outcomes. They may have significant implications for global public health and provide future dietary recommendations for the prevention of common chronic diseases.

Association between myeloperoxidase and the risks of ischemic stroke, heart failure, and atrial fibrillation: A Mendelian randomization study

Background and aimsThe causality between myeloperoxidase (MPO) and cardiovascular disease still remains unclear. We performed a two-sample Mendelian randomization (MR) study to estimate the potential causal effect of MPO on the risks of ischemic stroke, ischemic stroke subtypes, heart failure (HF), and atrial fibrillation (AF). Methods and resultsSeventeen independent single-nucleotide polymorphisms associated with MPO levels were identified as instrumental variables from a European-descent genome-wide association study. Summary-level data on ischemic stroke originated from the Multiancestry Genome-wide Association Study of Stroke Consortium with 440 328 European individuals. We used the inverse-variance weighted method to assess the potential causality of plasma MPO with ischemic stroke and its subtypes in the main analysis. Genetically determined higher plasma MPO concentration was significantly associated with increased risks of ischemic stroke (odds ratio [OR] per standard deviation [SD] increase, 1.05; 95% confidence interval [CI], 1.02–1.09; P = 0.002) and cardioembolic stroke (CES) (OR per SD increase, 1.10; 95% CI, 1.03–1.18; P = 0.005), but was not associated with risks of large artery stroke or small vessel stroke. In the secondary analysis, MPO was associated with a high risk of HF (OR per SD increase, 1.05; 95% CI, 1.02–1.07; P = 0.001) and AF (OR per SD increase, 1.04; 95% CI, 1.01–1.07; P = 0.004). MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses further confirmed these findings. ConclusionHigh plasma MPO levels were potentially associated with increased risks of ischemic stroke, CES, HF, and AF, suggesting that MPO plays an important role in the development of cardiovascular disease.

A saturated map of common genetic variants associated with human height

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Investigating genetic causal relationships between blood pressure and anxiety, depressive symptoms, neuroticism and subjective well-being

BackgroundHigh blood pressure is a leading cardiovascular disease risk factor and considered to be associated with psychological factors. However, the causal relationships between blood pressure and anxiety, depressive symptoms, neuroticism...

A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk.

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5× 10-8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR=1.22, 95%CI 1.13-1.32, P=4.81× 10-7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

Air pollutants, genetic susceptibility and risk of incident idiopathic pulmonary fibrosis.

Air pollutants are considered as non-negligible risk factors of idiopathic pulmonary fibrosis (IPF). However, the relationship between long-term air pollution and the incidence of IPF is unknown. Our objective was to explore the associations of air pollutants with IPF risk and further assess the modification effect of genetic susceptibility. We used land-use regression model estimated concentrations of nitrogen dioxide (NO2), nitrogen oxides (NO x ) and particulate matter (fine particulate matter with diameter <2.5 μm (PM2.5) and particulate matter with diameter <10 μm (PM10)). The polygenic risk score (PRS) was constructed using 13 independent single nucleotide polymorphisms. Cox proportional hazard models were used to evaluate the associations of air pollutants with IPF risk and further investigate the modification effect of genetic susceptibility. Additionally, absolute risk was calculated. Among 433 738 participants from the UK Biobank, the incidence of IPF was 27.45 per 100 000 person-years during a median follow-up of 11.78 years. The adjusted hazard ratios of IPF for each interquartile range increase in NO2, NO x and PM2.5 were 1.11 (95% CI 1.03-1.19), 1.07 (95% CI 1.01-1.13) and 1.09 (95% CI 1.02-1.17), respectively. PM2.5 had the highest population attribution risk, followed by NO x and NO2. There were additive interactions between NO2, NO x and PM2.5 and genetic susceptibility. Participants with a high PRS and high air pollution had the highest risk of incident IPF compared with those with a low PRS and low air pollution (adjusted hazard ratio: NO2 3.94 (95% CI 2.77-5.60), NO x 3.08 (95% CI 2.21-4.27), PM2.5 3.65 (95% CI 2.60-5.13) and PM10 3.23 (95% CI 2.32-4.50)). Long-term exposures to air pollutants may elevate the risk of incident IPF. There are additive effects of air pollutants and genetic susceptibility on IPF risk.

Causal relationship between insomnia and tuberculosis: A bi-directional Mendelian randomization analysis.

Previous observational studies appear to have established a bi-directional association between sleep disorders and tuberculosis. However, their conclusions are prone to be biased by confounding effects and reverse causation due to the nature of observational studies. Mendelian randomization (MR) approach provides unconfounded estimates of causal effects and overcomes the limitations of observational studies. We performed a bi-directional MR analysis to clarify whether there existed a causal effect of insomnia on tuberculosis, or tuberculosis on insomnia. In forward-direction MR, we chose genome-wide significant (P < .5 × 10-8) and independent (r2 < 0.001) single-nucleotide polymorphisms (SNPs) as instrumental variants (IVs), then extracted effect estimates of these IVs in tuberculosis genome-wide association study (GWAS) dataset to explore causal effect of genetically proxied insomnia on tuberculosis using inverse variance-weighted (IVW), MR-Egger, and weighted median methods. Additionally, we examined robustness and pleiotropy of effect estimates by heterogeneity and sensitivity analysis. Similarly, we investigated causal effect of genetically proxied tuberculosis on insomnia in reverse-direction MR. We revealed no causal relationship between genetically proxied insomnia and tuberculosis using 15 SNPs in forward-direction MR (IVW OR 5.305 [0.100-281.341], P = .410) and reverse-direction MR analysis (ORs and P values were not applicable due to no eligible SNPs in GWAS), with insignificant heterogeneity (Q = 22.6, I2 < 0.001, P = .066) and pleiotropy (intercept = 0.032, SE = 0.057, P = .592) in effect estimates. Our bi-directional MR analysis affirms no causal effect of insomnia on tuberculosis, or tuberculosis on insomnia.

Common genetic variants improve risk stratification after the atrial switch operation for transposition of the great arteries

BackgroundClinical factors are used to estimate late complication risk in adults after atrial switch operation (AtrSO) for transposition of the great arteries (TGA), but heterogeneity in clinical course remains. We studied whether common genetic variants are associated with outcome and add value to a clinical risk score in TGA-AtrSO patients. Methods and resultsThis multicenter study followed 133 TGA-AtrSO patients (aged 28 [IQR 24–35] years) for 13 (IQR 9–16) years and examined the association of genome-wide single-nucleotide polymorphisms (SNPs) with a composite endpoint of symptomatic ventricular arrhythmia, heart failure hospitalization, ventricular assist device implantation, heart transplantation, or mortality. Thirty-two patients (24%) reached the endpoint. The genome-wide association study yielded one genome-wide significant (p < 1 × 10−8) locus and 18 suggestive loci (p < 1 × 10−5). A genetic risk score constructed on the basis of independent SNPs with p < 1 × 10−5 was associated with outcome after correction for the clinical risk score (HR = 1.26/point increase [95%CI 1.17–1.35]). Risk stratification improved with a combined risk score (clinical score + genetic score) compared to the clinical score alone (p = 2 × 10−16, C-statistic 0.95 vs 0.85). In 51 patients with a clinical intermediate (5–20%) 5-year risk of events, the combined score reclassified 32 patients to low (<5%) and 5 to high (>20%) risk. Stratified by the combined score, observed 5-year event-free survival was 100%, 79% and 31% for low, intermediate, and high-risk patients, respectively. ConclusionsCommon genetic variants may explain some variation in the clinical course in TGA-AtrSO and improve risk stratification over clinical factors alone, especially in patients at intermediate clinical risk. These findings support the hypothesis that including genetic variants in risk assessment may be beneficial.