Subjects Of European Ancestry Research Articles

Brain lncRNA-mRNA co-expression regulatory networks and alcohol use disorder

Prolonged alcohol consumption can disturb the expression of both coding and noncoding genes in the brain. These dysregulated genes may co-express in modules and interact within networks, consequently influencing the susceptibility to developing alcohol use disorder (AUD). In the present study, we performed an RNA-seq analysis of the expression of both long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) in 192 postmortem tissue samples collected from eight brain regions (amygdala, caudate nucleus, cerebellum, hippocampus, nucleus accumbens, prefrontal cortex, putamen, and ventral tegmental area) of 12 AUD and 12 control subjects of European ancestry. Applying the limma-voom method, we detected a total of 57 lncRNAs and 51 mRNAs exhibiting significant differential expression (Padj < 0.05 and fold-change ≥2) across at least one of the eight brain regions investigated. Machine learning analysis further confirmed the potential of these top genes in predicting AUD. Through Weighted Gene Co-expression Network Analysis (WGCNA), we identified distinct lncRNA-mRNA co-expression modules associated with AUD in each of the eight brain regions. Additionally, lncRNA-mRNA co-expression networks were constructed for each brain region using Cytoscape to reveal gene regulatory interactions implicated in AUD. Hub genes within these networks were found to be enriched in several key KEGG pathways, including Axon Guidance, MAPK Signaling, p53 Signaling, Adherens Junction, and Neurodegeneration. Our results underscore the significance of networks involving AUD-associated lncRNAs and mRNAs in modulating neuroplasticity in response to alcohol exposure. Further elucidating these molecular mechanisms holds promise for the development of targeted therapeutic interventions for AUD.

Genome-wide association study and meta-analysis of phytosterols identifies a novel locus for serum levels of campesterol

Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of β-sitosterol and campesterol using the Metabolon platform from Qatar Biobank (QBB) and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms associated with β-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. Evaluation of a polygenic risk score devised from European GWAS data showed moderate performance when applied to QBB (adjusted-R2 = 0.082). These findings provide new insights into the genetic architecture of phytosterol metabolism while showing the importance including under-represented populations in future GWAS studies.

Objective Assessments of Smoking and Drinking Outperform Clinical Phenotypes in Predicting Variance in Epigenetic Aging.

The reliability of the associations of the acceleration of epigenetic aging (EA) indices with clinical phenotypes other than for smoking and drinking is poorly understood. Furthermore, the majority of clinical phenotyping studies have been conducted using data from subjects of European ancestry. In order to address these limitations, we conducted clinical, physiologic, and epigenetic assessments of a cohort of 278 middle-aged African American adults and analyzed the associations with the recently described principal-components-trained version of GrimAge (i.e., PC-GrimAge) and with the DunedinPACE (PACE) index using regression analyses. We found that 74% of PC-GrimAge accelerated aging could be predicted by a simple baseline model consisting of age, sex, and methylation-sensitive digital PCR (MSdPCR) assessments of smoking and drinking. The addition of other serological, demographic, and medical history variables or PACE values did not meaningfully improve the prediction, although some variables did significantly improve the model fit. In contrast, clinical variables mapping to cardiometabolic syndrome did independently contribute to the prediction of PACE values beyond the baseline model. The PACE values were poorly correlated with the GrimAge values (r = 0.2), with little overlap in variance explained other than that conveyed by smoking and drinking. The results suggest that EA indices may differ in the clinical information that they provide and may have significant limitations as screening tools to guide patient care.

Clinical and genetic risk factors for progressive fibrosis in metabolic dysfunction-associated steatotic liver disease.

Fibrosis-4 (FIB4) is a recommended noninvasive test to assess hepatic fibrosis among patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we used FIB4 trajectory over time (ie, "slope" of FIB4) as a surrogate marker of liver fibrosis progression and examined if FIB4 slope is associated with clinical and genetic factors among individuals with clinically defined MASLD within the Million Veteran Program Cohort. In this retrospective cohort study, FIB4 slopes were estimated through linear regression for participants with clinically defined MASLD and FIB4 <2.67 at baseline. FIB4 slope was correlated with demographic parameters and clinical outcomes using logistic regression and Cox proportional hazard models. FIB4 slope as a quantitative phenotype was used in a genome-wide association analysis in ancestry-specific analysis and multiancestry meta-analysis using METAL. FIB4 slopes, generated from 98,361 subjects with MASLD (16,045 African, 74,320 European, and 7996 Hispanic), showed significant associations with sex, ancestry, and cardiometabolic risk factors (p < 0.05). FIB4 slopes also correlated strongly with hepatic outcomes and were independently associated with time to cirrhosis. Five genetic loci showed genome-wide significant associations (p < 5 × 10-8) with FIB4 slope among European ancestry subjects, including 2 known (PNPLA3 and TM6SF2) and 3 novel loci (TERT 5.1 × 10-11; LINC01088, 3.9 × 10-8; and MRC1, 2.9 × 10-9). Linear trajectories of FIB4 correlated significantly with time to progression to cirrhosis, with liver-related outcomes among individuals with MASLD and with known and novel genetic loci. FIB4 slope may be useful as a surrogate measure of fibrosis progression.

Schizophrenia and risk preference: a bidirectional two-sample mendelian randomization study.

Increasing evidence shows that risk preference is associated with schizophrenia. However, the causality and direction of this association are not clear; Therefore, we used Mendelian randomization (MR) to examine the potential bidirectional relationship between risk preference and schizophrenia. Genome-wide association studies (GWAS) summary data on risk preference of 939,908 participants from the UK Biobank and 23andMe were used to identify general risk preference. Data from 320,404 subjects (76,755 cases and 243,649 controls) from The Psychiatric Genomics Consortium were used to identify schizophrenia. The weighted median (WM), the inverse variance weighted (IVW), and the Mendelian randomization-Egger (MR-Egger) methods were used for the MR analysis to estimate the causal effect and detect the directional pleiotropy. The GWAS summary data were respectively from two combined samples, containing 939,908 and 320,404 subjects of European ancestry. Mendelian randomization evidence suggested that risk preference was associated with increased onset of schizophrenia (OR = 2.84, 95CI%: 1.77-4.56, P = 1.58*10 - 5) and that schizophrenia was also associated with raised risk preference (OR = 1.11, 95CI%: 1.07-1.15, P = 7.98*10 - 8). With the use of large-scale GWAS data, robust evidence suggests an interaction between risk preference and schizophrenia. This also indicates that early identification of and intervention for increased risk preference may improve the prognosis of schizophrenia.

Novel Loci (EIF4A2, ADIPOQ, TPRG1) for Triglyceride / High-density Lipoprotein Cholesterol Ratio Longitudinal Change (ΔTHR) among Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Heart Study (FHS) Offspring Cohort (OS).

Triglyceride (TG) /High density lipoprotein cholesterol (HDL-C) ratio (THR) represents a single surrogate predictor of hyperinsulinemia or insulin resistance that is associated with premature aging processes, risk of diabetes and increased mortality. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among subjects of European ancestry who had complete data from two exams collected about seven years apart from the Long Life Family Study (LLFS, n=1384), a study with familial clustering of exceptional longevity in the US and Denmark. Subjects with diabetes or using medications for dyslipidemia were excluded from this analysis. ΔTHR was derived using growth curve modeling, and adjusted for age, sex, field centers, and principal components (PCs). GWAS was conducted using a linear mixed model accounted for familial relatedness. Our linkage scan was built on haplotype-based IBD estimation with 0.5 cM average spacing. Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (p=1.58e-9) for ΔTHR; this gene locus has been reported before influencing baseline THR levels. Our GWLS found evidence for a significant linkage with a logarithm of the odds (LODs) exceeding 3 on 3q28 (LODs=4.1). Using a subset of 25 linkage enriched families (pedigree-specific LODs>0.1), we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2/ADIPOQ-rs114108468, p=5e-6, MAF=1.8%; TPRG1-rs16864075, p=3e-6, MAF=8%; accounted for ~28% and ~29% of the linkage, respectively, and 57% jointly). While the former variant was associated with EIF4A2 (p=7e-5) / ADIPOQ (p=3.49e-2) RNA transcriptional levels, the latter variant was not associated with TPRG1 (p=0.23) RNA transcriptional levels. Replication in FHS OS observed modest effect of these loci on ΔTHR. Of 188 metabolites from 13 compound classes assayed in LLFS, we observed multiple metabolites (e.g., DG.38.5, PE.36.4, TG.58.3) that were significantly associated with the variants (p<3e-4). our linkage-guided sequence analysis approach permitted our discovery of two novel gene variants EIF4A2/ADIPOQ-rs114108468 and TPRG1-rs16864075 on 3q28 for ΔTHR among subjects without diabetes selected for exceptional survival and healthy aging.

LDER-GE estimates phenotypic variance component of gene-environment interactions in human complex traits accurately with GE interaction summary statistics and full LD information.

Gene-environment (GE) interactions are essential in understanding human complex traits. Identifying these interactions is necessary for deciphering the biological basis of such traits. In this study, we review state-of-art methods for estimating the proportion of phenotypic variance explained by genome-wide GE interactions and introduce a novel statistical method Linkage-Disequilibrium Eigenvalue Regression for Gene-Environment interactions (LDER-GE). LDER-GE improves the accuracy of estimating the phenotypic variance component explained by genome-wide GE interactions using large-scale biobank association summary statistics. LDER-GE leverages the complete Linkage Disequilibrium (LD) matrix, as opposed to only the diagonal squared LD matrix utilized by LDSC (Linkage Disequilibrium Score)-based methods. Our extensive simulation studies demonstrate that LDER-GE performs better than LDSC-based approaches by enhancing statistical efficiency by ~23%. This improvement is equivalent to a sample size increase of around 51%. Additionally, LDER-GE effectively controls type-I error rate and produces unbiased results. We conducted an analysis using UK Biobank data, comprising 307259 unrelated European-Ancestry subjects and 966766 variants, across 217 environmental covariate-phenotype (E-Y) pairs. LDER-GE identified 34 significant E-Y pairs while LDSC-based method only identified 23 significant E-Y pairs with 22 overlapped with LDER-GE. Furthermore, we employed LDER-GE to estimate the aggregated variance component attributed to multiple GE interactions, leading to an increase in the explained phenotypic variance with GE interactions compared to considering main genetic effects only. Our results suggest the importance of impacts of GE interactions on human complex traits.

Abstract LB226: Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition

Abstract Lung cancer is the leading cause of cancer-related mortality worldwide. Understanding lung cancer evolutionary dynamics can help identify tools to intercept its growth and suggest strategies for treatment. Multiple factors can impact the tumors’ natural history and distinctly affect growth rate. However, research on the evolutionary trajectories of lung cancer across demographic or exposure scenarios remains inadequate. Additionally, the roles of mutational processes and complex genomic alterations on the evolution of lung cancer are still largely unexplored. In the largest genomic study of lung cancer to date, we analyzed deep whole-genome sequencing (~ 81x) and other omics data of 1217 lung cancers from the Sherlock-Lung study. To ensure adequate statistical power for identifying subclone architectures and constructing lung cancer evolutionary histories, we utilized a metric known as NRPCC (number of reads per tumor chromosomal copy) to select 542 lung adenocarcinoma (LUAD) samples for clonal evolution analyses, including 186 and 181 samples from never-smoker subjects of European and Asian ancestry, respectively, and 121 samples from smokers of European ancestry. We found that major driver genes and exogenous mutations contribute to tumor initiation, while copy number gains and endogenous processes appear later in tumor evolution. Tumors harboring EGFR mutations in never-smoker females of European descent show long latency, while tumors with KRAS mutations have shorter latency regardless of ancestry and sex. Notably, tumors harboring the mutational signature ID2 have short latency and aggressive phenotype, accompanied by increased genomic instability, elevated hypoxia scores, high CpG methylator phenotype, low neoantigen burden, and propensity to develop metastasis. We show that LINE-1 retrotransposition-induced mutagenesis contributes to the origin of ID2 mutations. The transcriptional factor ZNF695, a member of the KZFP family, up-regulated in LUAD, appears to contribute to LINE-1 retrotransposition through a dominant-negative effect and LINE-1 promoter demethylation. In a multivariate analysis of genomics, exposures and demographic factors, LUAD latency was most significantly associated with ID2, followed by EGFR mutations, KRAS mutations, and sex, suggesting an independent impact of these factors on LUAD evolution. Our findings underscore the complex interplay of ancestry, sex, exogenous mutagenesis, epigenetic regulation, and LINE-1 retrotransposition in shaping LUAD evolutionary trajectories, paving the way for potential targeted therapeutic interventions. Citation Format: Tongwu Zhang, Wei Zhao, Christopher Wirth, Marcos Díaz-Gay, Jinhu Yin, Phuc H. Hoang, Jian Sang, John McElderry, Alyssa Klein, Azhar Khandekar, Caleb Hartman, Jennifer Rosenbaum, Frank Colon-Matos, Kristine M. Jones, Neil E. Caporaso, Robert Homer, Angela C. Pesatori, Dario Consonni, Lixing Yang, Bin Zhu, Jianxin Shi, Kevin Brown, Nathaniel Rothman, Stephen J. Chanock, Ludmil B. Alexandrov, Jiyeon Choi, Maurizio Cardelli, Qing Lan, Martin A. Nowak, David C. Wedge, Maria Teresa Landi. Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB226.

Abstract 7010: A pan-tissue investigation of epigenetic aging in association with genetic risk for cancer among European descendants

Abstract Epigenetic age (EA) is recognized as a valuable biomarker of aging. The discrepancy between epigenetic and chronological age (CA), termed epigenetic age acceleration (EAA), has been associated with increased mortality from various age-related diseases, including cancer. However, previous studies primarily focused on the EA in blood cells, resulting in a notable gap in understanding the EA in cancer-relevant tissues and its relationship to cancer development. To examine if genetic risks for seven distinct cancers are associated with EAA in cancer-relevant tissues and blood cells, we utilized Illumina EPIC-array-based DNA methylation data and whole genome sequencing (WGS)-derived genotype data of 659 normal tissue and 42 whole blood samples from 315 European-ancestry subjects in the Genotype-Tissue Expression (GTEx) project. EA was estimated across 30 female breast, 167 colon, 41 kidney, 163 lung, 118 ovary, 96 prostate, 44 testis, and 42 whole blood samples via seven established epigenetic clocks: HorvathAge, GrimAge, GrimAge2, HannumAge, PhenoAge, Zhang-BLUP-Age, and Zhang-EN-Age. EAA was calculated as the residual of EA regressed on CA. For each participant, a polygenic risk score (PRS) was computed to assess the genetic risk for each cancer, using validated cancer-specific PRSs for European populations from the Polygenic Score Catalogue. Linear regression analysis was performed to evaluate the association between cancer PRS and EAA, adjusting for body mass index, sex (where applicable), cigarette smoking, and WGS platform and library construction protocol. All EA estimates of cancer-relevant tissues and blood cells exhibited significant correlations with CA (maximum P=2.44 × 10−3). Among them, GrimAge, known for its strong predictive capacity for mortality, had the most pronounced correlation with CA, with Spearman coefficients ranging from 0.80 in blood cells to 0.98 in breast tissues. A higher prostate cancer PRS was significantly associated with increased EAA in normal prostate tissues measured by PhenoAge (β=2.49; P=0.01), Zhang-BLUP-Age (β=1.71; P=0.02), HannumAge (β=1.36; P=0.04), and GrimAge (β=0.73; P=0.04). In addition, a higher PRS for renal cell carcinoma showed a significant association with increased GrimAge acceleration in normal kidney tissues (β=0.82; P=0.02). Moreover, breast and lung cancer PRSs were significantly associated with increased EAA in blood cells. Specifically, breast cancer PRS was associated with Zhang-BLUP-Age acceleration (β=0.99; P=0.04), while lung cancer PRS showed associations with HannumAge (β=1.78; P=0.01) and Zhang-EN-Age acceleration (β=0.94; P=0.02). Our results suggest a potential connection between genetic susceptibility to certain cancers and accelerated aging in relevant tissues and/or blood cells before cancer onset. Future large-scale studies are needed to substantiate and expand upon our findings. Citation Format: Yaxin Chen, Yawen Qi, Gang Wang, Yufang Xie, Yaohua Yang, Weimin Li. A pan-tissue investigation of epigenetic aging in association with genetic risk for cancer among European descendants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7010.

Independent causal effect of remnant cholesterol on atherosclerotic cardiovascular outcomes: a Mendelian randomization study

Abstract Background Observational studies suggested that residual risk of cardiovascular events following LDL-cholesterol (LDL-C) lowering may be linked to remnant cholesterol (RC). Purpose We conducted a large-scale Mendelian Randomization (MR) study to investigate the causal role of RC to predict coronary artery disease (CAD), myocardial infarction (MI) and stroke risk. Methods Outcome sources included 19,273 subjects of European ancestry from 14 cohorts, as well as data in 115,078 individuals from the OpenGWAS public data infrastructure. Over 12,000,000 SNPs were screened. We estimated the genetic association with outcomes from the Coronary Artery Disease (C4D) Genetics (CARDIoGRAMplusC4D) consortium, the Metastroke consortium as well as the Global Lipids Genetics Consortium. Our approach was to use genetic variants as instruments, thereby minimizing residual confounding, and reverse causation biases of observational studies. Results By leveraging data from a combined sample of ∼917,000 participants, we found evidence for a significant causal effect of RC on the risk of CAD (OR 1.51 per each mg/dL unit increase in RC, 95% CI 1.42–1.60), MI (OR 1.57, 1.21–2.05) and stroke (OR 1.23,1.12–1.35). There was no evidence of pleiotropy. Mediation analysis showed that the total effect of RC on CAD and MI was mainly direct: ORDirect 1.49 (1.37-1.61) for CAD and ORDirect 1.80 (1.70-19.1) for MI without a meaningful indirect effect exerted on these outcomes via the LDL-C mediator. Lifelong genetic inhibition of RC led to a 40% MI risk reduction which is superior to any intensity of pharmacological reduction from clinical trials with an average 3.5 years follow-up. Conclusions This large-scale MR study showed a robust genetic causal association between RC and cardiovascular outcomes. The effect on CAD and MI is independent of LDL-C. Early screening for RC along with long-term inhibition of RC should be the focus of future therapeutic interventions.

Increased Frequency of the HLA-DRB1*04:04-DQA1*03-DQB1*03:02 Haplotype Among HLA-DQB1*06:02-Positive Children With Type 1 Diabetes.

HLA DR-DQ haplotypes largely define genetic susceptibility to type 1 diabetes (T1D). The DQB1*06:02 positive haplotype (DR15-DQ602) common in subjects of European ancestry is very rare among children with T1D. Among 4490 children with T1D in the Finnish Pediatric Diabetes Register 57 (1.3%) cases with DQB1*06:02 were identified in comparison to 26.1% of affected family-based association controls. There was no difference between DQB1*06:02 positive and negative children with T1D regarding sex, age, islet autoantibody distribution or autoantibody levels, but significant differences were seen in the frequency of the second class II HLA haplotypes. The most prevalent haplotype present with DQB1*06:02 was DRB1*04:04-DQA1*03-DQB1*03:02 which was found in 27 of 57 (47.4%) children compared to only 797/4433 (18.0%) among DQB1*06:02 negative cases (P<0.001, Chi-square test). The other common risk associated haplotypes, the DRB1*04:01-DQA1*03-DQB1*03:02 and (DR3)-DQA1*05-DQB1*02 were less prevalent in DQB1*06:02 positive than DQB1*06:02 negative children (P<0.001). HLA-B allele frequencies did not differ between DQB1*06:02 haplotypes in children with T1D and controls and neither in DRB1*04:04-DQA1*03-DQB1*03:02 haplotypes of DQB1*06:02 positive and negative T1D children. The increased frequency of DRB1*04:04 allele among DQB1*06:02 positive cases may indicate preferential ability of the DR404 molecule to present islet antigen epitopes despite of the competition by DQ602.

Genetics of Pulmonary Pressure and Right Ventricle Stress Identify Diabetes as a Causal Risk Factor.

Background Epidemiologic studies have identified risk factors associated with pulmonary hypertension and right heart failure, but causative drivers of pulmonary hypertension and right heart adaptation are not well known. We sought to leverage unbiased genetic approaches to determine clinical conditions that share genetic architecture with pulmonary pressure and right ventricular dysfunction. Methods and Results We leveraged Vanderbilt University's deidentified electronic health records and DNA biobank to identify 14 861 subjects of European ancestry who underwent at least 1 echocardiogram with available estimates of pulmonary pressure and right ventricular function. Analyses of the study were performed between 2020 and 2022. The final analytical sample included 14 861 participants (mean [SD] age, 63 [15] years and mean [SD] body mass index, 29 [7] kg/m2). An unbiased phenome-wide association study identified diabetes as the most statistically significant clinical International Classifications of Diseases, Ninth Revision (ICD-9) code associated with polygenic risk for increased pulmonary pressure. We validated this finding further by finding significant associations between genetic risk for diabetes and a related condition, obesity, with pulmonary pressure estimate. We then used 2-sample univariable Mendelian randomization and multivariable Mendelian randomization to show that diabetes, but not obesity, was independently associated with genetic risk for increased pulmonary pressure and decreased right ventricle load stress. Conclusions Our findings show that genetic risk for diabetes is the only significant independent causative driver of genetic risk for increased pulmonary pressure and decreased right ventricle load stress. These findings suggest that therapies targeting genetic risk for diabetes may also potentially be beneficial in treating pulmonary hypertension and right heart dysfunction.

Shared genetic architecture of blood eosinophil counts and asthma in UK Biobank.

Asthma is a complex, heterogeneous disease strongly associated with type 2 inflammation, and blood eosinophil counts guide therapeutic interventions in moderate and severe asthma. Eosinophils are leukocytes involved in type 2 immune responses. Despite these critical associations between asthma and blood eosinophil counts, the shared genetic architecture of these two traits remains unknown. The objective of the present study was to characterise the genetic architecture of blood eosinophil counts and asthma in the UK Biobank. We performed genome-wide association studies (GWAS) of doctor-diagnosed asthma, blood eosinophil, neutrophil, lymphocyte and monocyte counts in the UK Biobank. Genetic correlation analysis was performed on GWAS results and validated in the Trans-National Asthma Genetic Consortium (TAGC) study of asthma. GWAS of doctor-diagnosed asthma and blood eosinophil counts in the UK Biobank identified 585 and 3429 significant variants, respectively. STAT6, a transcription factor involved in interleukin-4 signalling, was a key shared pathway between asthma and blood eosinophil counts. Genetic correlation analysis demonstrated a positive correlation between doctor-diagnosed asthma and blood eosinophil counts (r=0.38±0.10, correlation±se; p=4.7×10-11). As a validation of this association, we found a similar correlation between TAGC and blood eosinophil counts in the UK Biobank (0.37±0.08, correlation±se; p=1.2×10-6). These findings define the shared genetic architecture between blood eosinophil counts and asthma risk in subjects of European ancestry and point to a genetic link to the STAT6 signalling pathway in these two traits.

The relationship between blood lipid and risk of psoriasis: univariable and multivariable Mendelian randomization analysis.

Psoriasis is a chronic inflammatory skin disease. Dyslipidemia may be a risk factor of psoriasis. But the causal relationship between psoriasis and blood lipid still remains uncertain. The two data of blood lipid were obtained from UK Biobank (UKBB) and Global Lipid Genetics Consortium Results (GLGC). The primary and secondary database were from large publicly available genome-wide association study (GWAS) with more than 400,000 and 170,000 subjects of European ancestry, respectively. The psoriasis from Finnish biobanks of FinnGen research project for psoriasis, consisting of 6,995 cases and 299,128 controls. The single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) were used to assess the total and direct effects of blood lipid on psoriasis risk. SVMR estimates in primary data of blood lipid showed low-density lipoprotein cholesterol (LDL-C) (odds ratio (OR): 1.11, 95%, confidence interval (CI): 0.99-1.25, p = 0.082 in stage 1; OR: 1.15, 95% CI: 1.05-1.26, p = 0.002 in stage 2; OR: 1.15, 95% CI: 1.04-1.26, p = 0.006 in stage 3) and triglycerides (TG) (OR: 1.22, 95% CI: 1.10-1.35, p = 1.17E-04 in stage 1; OR: 1.15, 95% CI: 1.06-1.24, p = 0.001 in stage 2; OR: 1.14, 95% CI: 1.05-1.24, p = 0.002 in stage 3) had a highly robust causal relationship on the risk of psoriasis. However, there were no robust causal associations between HDL-C and psoriasis. The SVMR results in secondary data of blood lipid were consistent with the primary data. Reverse MR analysis showed a causal association between psoriasis and LDL-C (beta: -0.009, 95% CI: -0.016- -0.002, p = 0.009) and HDL-C (beta: -0.011, 95% CI: -0.021- -0.002, p = 0.016). The reverse causation analyses results between psoriasis and TG did not reach significance. In MVMR of primary data of blood lipid, the LDL-C (OR: 1.05, 95% CI: 0.99-1.25, p = 0.396 in stage 1; OR: 1.07, 95% CI: 1.01-1.14, p = 0.017 in stage 2; OR: 1.08, 95% CI: 1.02-1.15, p = 0.012 in stage 3) and TG (OR: 1.11, 95% CI: 1.01-1.22, p = 0.036 in stage 1; OR: 1.09, 95% CI: 1.03-1.15, p = 0.002 in stage 2; OR: 1.07, 95% CI: 1.01-1.13 p = 0.015 in stage 3) positively correlated with psoriasis, and there had no correlation between HDL-C and psoriasis. The results of the secondary analysis were consistent with the results of primary analysis. Mendelian randomization (MR) findings provide genetic evidence for causal link between psoriasis and blood lipid. It may be meaningful to monitor and control blood lipid level for a management of psoriasis patients in clinic.

Common genetic variants contribute to heritability of age at onset of schizophrenia

Schizophrenia (SCZ) is a complex disorder that typically arises in late adolescence or early adulthood. Age at onset (AAO) of SCZ is associated with long-term outcomes of the disease. We explored the genetic architecture of AAO with a genome-wide association study (GWAS), heritability, polygenic risk score (PRS), and copy number variant (CNV) analyses in 4 740 subjects of European ancestry. Although no genome-wide significant locus was identified, SNP-based heritability of AAO was estimated to be between 17 and 21%, indicating a moderate contribution of common variants. We also performed cross-trait PRS analyses with a set of mental disorders and identified a negative association between AAO and common variants for SCZ, childhood maltreatment and attention-deficit/hyperactivity disorder. We also investigated the role of copy number variants (CNVs) in AAO and found an association with the length and number of deletions (P-value = 0.03), whereas the presence of CNVs previously reported in SCZ was not associated with earlier onset. To our knowledge, this is the largest GWAS of AAO of SCZ to date in individuals from European ancestry, and the first study to determine the involvement of common variants in the heritability of AAO. Finally, we evidenced the role played by higher SCZ load in determining AAO but discarded the role of pathogenic CNVs. Altogether, these results shed light on the genetic architecture of AAO, which needs to be confirmed with larger studies.

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10-9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3- B cells, CD5+IgD- cells, IgM- cells, IgD-IgM- cells, and CD4-CD8- PBMCs (p = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent pathways.

PO-455617-3 NOVEL PRECISION GENETIC APPROACH IMPROVES DIAGNOSIS AND RISK STRATIFICATION IN LONG QT SYNDROME TYPE 5

Type 5 long QT syndrome (LQT5) is a subtype of long QT syndrome caused by loss of function variants in KCNE1 encoding a key potassium channel function-modifying subunit. LQT5 cases are rare and incompletely penetrant, so it has been controversial whether KCNE1 variants are disease-causing or risk-modifying. We identified 9 local LQT5 probands carrying the D76N KCNE1 variant, the most common variant implicated in LQT5. To test the hypothesis that these probands shared a recent common ancestor and to identify other potential D76N carriers in BioVU, our biobank that links electronic health records to DNA data. We used dense genomic arrays and identity-by-descent (IBD)-based genotype inference to identify shared chromosomal segments in the 9 probands and 3 first-degree relatives, and across BioVU. We determined penetrance (QTc > 490 msec) and the relationship of penetrance to a 1.1 million SNP QT interval polygenic risk score (PRS) in all mutation carriers. IBD analysis identified large (>1 cM) shared chromosomal segments across 8 of the 9 probands, indicating a shared common ancestor approximately 4-5 generations ago. Interrogation of array data in 69,879 European ancestry subjects in BioVU identified a further 26 subjects sharing the same large chromosomal segment, and sequencing confirmed D76N carrier status in 22 subjects, all previously undiagnosed. One BioVU subject had a history of sotalol-induced Torsades de Pointes. We found that among the 34 D76N carriers, QT intervals were prolonged compared to >32,000 BioVU controls free of heart disease or QT prolonging drugs, and that penetrance for QTc>490 was 44%. Among carriers, the QTc PRS was associated with severe QT prolongation. Detection of large shared chromosomal segments around KCNE1 enabled us to define a local founder event, identify previously undiagnosed carriers, demonstrate the contribution of polygenic risk to monogenic disease penetrance, and to further establish LQT5 as a primary arrhythmia disorder. The analysis of distant relatedness is a promising new approach to identify undiagnosed cases of genetic diseases.

Genetically predicted circulating levels of cytokines and the risk of osteoarthritis: A mendelian randomization study.

Background: The association between inflammatory cytokines and osteoarthritis (OA) has been reported in several observational studies, but the causal relationship between these two remains unknown. Hence, we performed this two-sample Mendelian randomization (MR) to confirm the causal relationship between circulating levels of inflammatory factors and osteoarthritis risk. Method: We used genetic variants associated with cytokine circulation levels from a meta-analysis of genome-wide association studies (GWASs) in 8,293 Finns as instrumental variables and obtained OA data from the United Kingdom Biobank, including a total of 345,169 subjects of European ancestry (66,031 diagnosed OA cases and 279,138 controls). Inverse variance weighting (IVW), MR-Egger, Wald Ratio, weighted median, and MR multiplicity residual sums with outliers (MR-PRESSO) were used. Result: We found a causal relationship between circulating levels of macrophage inflammatory protein-1beta (MIP-1β) and risk of OA (OR = 0.998, 95% CI = 0.996-0.999p = 9.61 × 10-5); tumour necrosis factor beta (TNF-β) was also causally associated with risk of OA (OR = 0.996,95%CI = 0.994-0.999, p = 0.002); finally we found a suggestive association between C-C motif chemokine ligand 5(CCL5, also called Rantes) and OA risk (OR = 1.013, 95%CI = 1.002-1.024,p = 0.016). Conclusion: Our findings offer promising leads for the development of new therapeutic targets in the treatment of osteoarthritis. By identifying the role of inflammatory cytokines in this debilitating condition through a genetic epidemiological approach, our study contributes to a better understanding of the underlying disease mechanisms. These insights may ultimately pave the way for more effective treatments that improve patient outcomes.

X chromosome associations with chronic obstructive pulmonary disease and related phenotypes: an X chromosome-wide association study

BackgroundThe association between genetic variants on the X chromosome to risk of COPD has not been fully explored. We hypothesize that the X chromosome harbors variants important in determining risk of COPD related phenotypes and may drive sex differences in COPD manifestations.MethodsUsing X chromosome data from three COPD-enriched cohorts of adult smokers, we performed X chromosome specific quality control, imputation, and testing for association with COPD case–control status, lung function, and quantitative emphysema. Analyses were performed among all subjects, then stratified by sex, and subsequently combined in meta-analyses.ResultsAmong 10,193 subjects of non-Hispanic white or European ancestry, a variant near TMSB4X, rs5979771, reached genome-wide significance for association with lung function measured by FEV1/FVC (beta 0.020, SE 0.004, p 4.97 × 10–08), with suggestive evidence of association with FEV1 (beta 0.092, SE 0.018, p 3.40 × 10–07). Sex-stratified analyses revealed X chromosome variants that were differentially trending in one sex, with significantly different effect sizes or directions.ConclusionsThis investigation identified loci influencing lung function, COPD, and emphysema in a comprehensive genetic association meta-analysis of X chromosome genetic markers from multiple COPD-related datasets. Sex differences play an important role in the pathobiology of complex lung disease, including X chromosome variants that demonstrate differential effects by sex and variants that may be relevant through escape from X chromosome inactivation. Comprehensive interrogation of the X chromosome to better understand genetic control of COPD and lung function is important to further understanding of disease pathology.Trial registration Genetic Epidemiology of COPD Study (COPDGene) is registered at ClinicalTrials.gov, NCT00608764 (Active since January 28, 2008). Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints Study (ECLIPSE), GlaxoSmithKline study code SCO104960, is registered at ClinicalTrials.gov, NCT00292552 (Active since February 16, 2006). Genetics of COPD in Norway Study (GenKOLS) holds GlaxoSmithKline study code RES11080, Genetics of Chronic Obstructive Lung Disease.

Genome-wide assessment reveals a significant association between ACSS3 and physical activity.

Recent genetic studies have identified physical activity (PA)-susceptible loci in European ancestry subjects; however, due to considerable genetic differences, these findings are not likely extendable to East Asian populations. Therefore, the present study aimed to identify significantly associated PA-susceptible loci using genome-wide association studies (GWASs) with East Asian (EAS) subjects and to generalize the findings to European (EUR) ancestries. The mRNA levels of genes located near the genome-wide significantly associated single-nucleotide polymorphisms (SNP) were compared under PA and control conditions. Rs74937256, located in ACSS3 (chromosome 12), which primarily functions in skeletal muscle tissues, was identified as a genome-wide significant variant (P=6.06 × 10-9 ) in EAS. Additionally, the rs2525840, also in ACSS3 satisfied the Bonferroni corrected significance (P= 3.77 × 10-5 ) in EUR. We found that rs74937256 is an expressed trait locus of ACSS3 (P=10-4 ), and ACSS3 mRNA expression significantly differs after PA, based on PrediXcan (P=7 × 10-8 ) and the gene expression omnibus database (P=0.043).