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Background: Inflammation is thought to be a risk factor for kidney disease. However, whether inflammatory status is either a cause or an outcome of chronic kidney disease remains controversial. We aimed to investigate the causal relationship between high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) using Mendelian randomization (MR) approaches. Methods: A total of 10,521 participants of the Japan Multi-institutional Collaborative Cohort Study was analyzed in this study. We used two-sample MR approaches (the inverse-variance weighted (IVW), the weighted median (WM), and the MR-Egger method) to estimate the effect of genetically determined hs-CRP on kidney function. We selected four and three hs-CRP associated single nucleotide polymorphisms (SNPs) as two instrumental variables (IV): IVCRP and IVAsian, based on SNPs previously identified in European and Asian populations. IVCRP and IVAsian explained 3.4% and 3.9% of the variation in hs-CRP, respectively. Results: Using the IVCRP, genetically determined hs-CRP was not significantly associated with eGFR in the IVW and the WM methods (estimate per 1 unit increase in ln(hs-CRP), 0.000; 95% confidence interval [CI], −0.019 to 0.020 and −0.003; 95% CI, −0.019 to 0.014, respectively). For IVAsian, we found similar results using the IVW and the WM methods (estimate, 0.005; 95% CI, −0.020 to 0.010 and −0.004; 95% CI, −0.020 to 0.012, respectively). The MR-Egger method also showed no causal relationships between hs-CRP and eGFR (IVCRP: −0.008; 95% CI, −0.058 to 0.042; IVAsian: 0.001; 95% CI, −0.036 to 0.036). Conclusion: Our two-sample MR analyses with different IVs did not support a causal effect of hs-CRP on eGFR.

RATIONALE: The course of lung function, respiratory symptoms, and functional status over time in people who smoke cigarettes is still incompletely understood. The COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]) study provides a unique cohort to examine these trajectories, and now 10-year follow-up data are available. OBJECTIVES: This study aims to provide insight into the progression of spirometric parameters, respiratory symptoms, and functional capacity over 10 years in current and former cigarette smokers. METHODS: We analyzed available longitudinal data for COPDGene participants who did not change smoking status over three visits spanning approximately 10 years of follow-up. Change in postbronchodilator forced expiratory volume in 1 second (FEV(1)), St. George’s Respiratory Questionnaire (SGRQ), and 6-minute walk distance (6MWD) from Phase 1 to Phase 3 were examined using linear mixed models. Terms were included in the models to estimate mean progression separately for current and former cigarette smokers. Models were stratified by baseline Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometry stages as well as by new 2019 COPDGene classification. RESULTS: The mean age at enrollment of the 9,103 participants in this analysis was 59.8 years (SD = 9.2 yr); 46.4% were women, and 32.6% were African American. In all GOLD COPD groups, including participants with normal spirometry, and all groups categorized by 2019 COPDGene classification, FEV(1) decreased, SGRQ increased (indicating higher symptom burden), and 6MWD decreased over the 10-year follow-up period. Current smokers exhibited a greater mean loss of FEV(1) over the study period than former smokers for all groups except those with preserved ratio impaired spirometry. For both SGRQ and 6MWD, rates of progression tended to be similar for former and current smokers except for 6MWD in the highest severity groups, in which former smokers had greater progression. However, this could be impacted by some current smokers with faster progression who had quit smoking and were dropped from analyses. CONCLUSIONS: Progression in FEV(1), SGRQ, and 6MWD overall appears to be slow, and the change over time in groups traditionally characterized as not having disease closely mirrors that of the groups with COPD at all GOLD stages. Current cigarette smokers had greater loss of FEV(1) than former smokers, whereas SGRQ and 6MWD changes were more similar between current and former cigarette smokers.

Measurement of circulating immunoglobulin E (IgE) concentration is helpful for diagnosing and treating asthma and allergic diseases. Identifying gene expression signatures associated with IgE might elucidate novel pathways for IgE regulation. To this end, we performed a discovery transcriptome-wide association study to identify differentially expressed genes associated with circulating IgE levels in whole-blood derived RNA from 5,345 participants in the Framingham Heart Study across 17,873 mRNA gene-level transcripts. We identified 216 significant transcripts at a false discovery rate CLC, CCDC21, S100A13, and GCNT1) as putatively causal (pGCNT1 (beta=1.5, p=0.01)—which is a top result in the MR analysis of expression in relation to asthma and allergic diseases—plays a role in regulating T helper type 1 cell homing, lymphocyte trafficking, and B cell differentiation. Our findings build upon prior knowledge of IgE regulation and provide a deeper understanding of underlying molecular mechanisms. The IgE-associated genes that we identified—particularly those implicated in MR analysis—can be explored as promising therapeutic targets for asthma and IgE-related diseases.

Background Heart failure (HF) is one of the most common complications of cardiovascular diseases (CVDs) and among the leading causes of death in the US. Many other CVDs can lead to increased mortality as well. Investigating the genetic epidemiology and susceptibility to CVDs is a central focus of cardiology and biomedical life sciences. Several studies have explored expression of key CVD genes specially in HF, yet new targets and biomarkers for early diagnosis are still missing to support personalized treatment. Lack of gender-specific cardiac biomarker thresholds in men and women may be the reason for CVD underdiagnosis in women, and potentially increased morbidity and mortality as a result, or conversely, an overdiagnosis in men. In this context, it is important to analyze the expression and enrichment of genes with associated phenotypes and disease-causing variants among high-risk CVD populations. Methods We performed RNA sequencing focusing on key CVD genes with a great number of genetic associations to HF. Peripheral blood samples were collected from a broad age range of adult male and female CVD patients. These patients were clinically diagnosed with CVDs and CMS/HCC HF, as well as including cardiomyopathy, hypertension, obesity, diabetes, asthma, high cholesterol, hernia, chronic kidney, joint pain, dizziness and giddiness, osteopenia of multiple sites, chest pain, osteoarthritis, and other diseases. Results We report RNA-seq driven case–control study to analyze patterns of expression in genes and differentiating the pathways, which differ between healthy and diseased patients. Our in-depth gene expression and enrichment analysis of RNA-seq data from patients with mostly HF and other CVDs on differentially expressed genes and CVD annotated genes revealed 4,885 differentially expressed genes (DEGs) and regulation of 41 genes known for HF and 23 genes related to other CVDs, with 15 DEGs as significantly expressed including four genes already known (FLNA, CST3, LGALS3, and HBA1) for HF and CVDs with the enrichment of many pathways. Furthermore, gender and ethnic group specific analysis showed shared and unique genes between the genders, and among different races. Broadening the scope of the results in clinical settings, we have linked the CVD genes with ICD codes. Conclusions Many pathways were found to be enriched, and gender-specific analysis showed shared and unique genes between the genders. Additional testing of these genes may lead to the development of new clinical tools to improve diagnosis and prognosis of CVD patients.

Considerable recent advancements in elucidating the genetic architecture of sleep traits and sleep disorders may provide insight into the relationship between sleep and obesity. Despite the involvement of the circadian clock in sleep and metabolism, few shared genes, including FTO, were implicated in genome-wide association studies (GWASs) of sleep and obesity. Polygenic scores composed of signals from GWASs of sleep traits show largely null associations with obesity, suggesting lead variants are unique to sleep. Modest genome-wide genetic correlations are observed between many sleep traits and obesity and are largest for snoring. Notably, U-shaped positive genetic correlations with body mass index (BMI) exist for both short and long sleep durations. Findings from Mendelian randomization suggest robust causal effects of insomnia on higher BMI and, conversely, of higher BMI on snoring and daytime sleepiness. In addition, bidirectional effects between sleep duration and daytime napping with obesity may also exist. Limited gene-sleep interaction studies suggest that achieving favorable sleep, as part of a healthy lifestyle, may attenuate genetic predisposition to obesity,but whether these improvements produce clinically meaningful reductions in obesity risk remains unclear. Investigations of the genetic link between sleep and obesity for sleep disorders other than insomnia and in populations of non-European ancestry are currently limited.

The prevalence and contribution of BRCA1/2 (BRCA) pathogenic variants (PVs) to the cancer burden in Latin America are not well understood. This study aims to address this disparity. BRCA analyses were performed on prospectively enrolled Latin American Clinical Cancer Genomics Community Research Network participants via a combination of methods: a Hispanic Mutation Panel (HISPANEL) on MassARRAY; semiconductor sequencing; and copy number variant (CNV) detection. BRCA PV probability was calculated using BRCAPRO. Among 1,627 participants (95.2% with cancer), we detected 236 (14.5%) BRCA PVs; 160 BRCA1 (31% CNVs); 76 BRCA2 PV frequency varied by country: 26% Brazil, 9% Colombia, 13% Peru, and 17% Mexico. Recurrent PVs (seen ≥3 times), some region-specific, represented 42.8% (101/236) of PVs. There was no ClinVar entry for 14% (17/125) of unique PVs, and 57% (111/196) of unique VUS. The area under the ROC curve for BRCAPRO was 0.76. In summary, we implemented a low-cost BRCA testing strategy and documented a significant burden of non-ClinVar reported BRCA PVs among Latin Americans. There are recurrent, population-specific PVs and CNVs, and we note that the BRCAPRO mutation probability model performs adequately. This study helps address the gap in our understanding of BRCA-associated cancer in Latin America.

Here, we report the first population genetic study to examine the impact of indoor residual spraying (IRS) on Plasmodium falciparum in humans. This study was conducted in an area of high seasonal malaria transmission in Bongo District, Ghana. IRS was implemented during the dry season (November–May) in three consecutive years between 2013 and 2015 to reduce transmission and attempt to bottleneck the parasite population in humans towards lower diversity with greater linkage disequilibrium. The study was done against a background of widespread use of long‐lasting insecticidal nets, typical for contemporary malaria control in West Africa. Microsatellite genotyping with 10 loci was used to construct 392 P. falciparum multilocus infection haplotypes collected from two age‐stratified cross‐sectional surveys at the end of the wet seasons pre‐ and post‐IRS. Three‐rounds of IRS, under operational conditions, led to a >90% reduction in transmission intensity and a 35.7% reduction in the P. falciparum prevalence (p

Objectives Up to 0.3% of Japanese have hypouricaemia. Most cases appear to result from a hereditary disease, renal hypouricaemia (RHUC), which causes exercise-induced acute kidney injury and urolithiasis. However, to what extent RHUC accounts for hypouricaemia is not known. We therefore investigated its frequency and evaluated its risks by genotyping a general Japanese population. Methods A cohort of 4993 Japanese was examined by genotyping the non-functional variants R90H (rs121907896) and W258X (rs121907892) of URAT1/SLC22A12, the two most common causative variants of RHUC in Japanese. Results Participants’ fractional excretion of uric acid and risk allele frequencies markedly increased at lower serum uric acid (SUA) levels. Ten participants (0.200%) had an SUA level ≤2.0 mg/dl and nine had R90H or W258X and were likely to have RHUC. Logistic regression analysis revealed these URAT1 variants to be significantly and independently associated with the risk of hypouricaemia and mild hypouricaemia (SUA ≤3.0 mg/dl) as well as sex, age and BMI, but these URAT1 variants were the only risks in the hypouricaemia population (SUA ≤2.0 mg/dl). W258X was only a risk in males with SUA ≤3.0 mg/dl. Conclusion Our study accurately reveals the prevalence of RHUC and provides genetic evidence for its definition (SUA ≤2.0 mg/dl). We also show that individuals with SUA ≤3.0 mg/dl, especially males, are prone to RHUC. Our findings will help to promote a better epidemiological understanding of RHUC as well as more accurate diagnosis, especially in males with mild hypouricaemia.

Immigration impact on genetic epidemiology of thalassemia worldwide is well-recognized. Over the past decade, the Duhok Province of Northern Iraq attracted a large number of immigrants. To assess whether immigration had contributed to changes in the mutation spectrum of β-thalassemia (β-thal) in the region, we recruited 218 registered patients with symptomatic β-thal. The recruited patients included 50 (22.9%) from resettled migrant families. A total of 431 β-thal alleles were fully characterized, with 20 different thalassemia mutations, the most frequent being IVS-II-1 (G>A) (HBB: c.315 + 1G>A), IVS-I-6 (T>C) (HBB: c.92 + 6T>C), codon 5 (-CT) (HBB: c.17_18delCT), IVS-I-110 (G>A) (HBB: c.93-21G>A), codon 44 (-C) (HBB: c.135delC), codon 8 (-AA) (HBB: c.25_26delAA) and IVS-I-1 (G>A) (HBB: c.92 + 1G>A) constituting 72.8% of the total. Some differences in mutation spectrum were observed compared to earlier studies from this same province, the most notable of which were the higher frequencies of IVS-I-110 and codon 8. Interestingly, the highest proportions of alleles related to immigrants were encountered in these two allele groups. Ethnic variation was also documented, so that while Muslim Kurds had IVS-II-1, IVS-I-6, IVS-I-110, codon 5 and codon 44 as their most frequent mutations, the most frequent among Kurdish Yazidis, were codon 5, codon 44, codon 8 and IVS-I-6. These ethnic variations and changes in mutation spectrums are important and should be taken in consideration to ensure effective implementation of the thalassemia preventive program.

Highlights • Two-sample Mendelian randomization approaches have been utilized to explore the causal relationship between accelerometer-measured physical activity and 3 common neurodegenerative diseases. • We found no evidence for the casual effect of physical activity on the risk of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in the European population. • Genetically predicted physical activity was not robustly associated with the risk of 3 common neurodegenerative disorders., Background Physical activity has been hypothesized to play a protective role in neurodegenerative diseases. However, effect estimates previously derived from observational studies were prone to confounding or reverse causation. Methods We performed a two-sample Mendelian randomization (MR) analysis to explore the causal association of accelerometer-measured physical activity with 3 common neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). We selected genetic instrumental variants reaching genome-wide significance (p < 5 × 10−8) from 2 largest meta-analyses of about 91,100 UK Biobank participants. Summary statistics for AD, PD, and ALS were retrieved from the up-to-date studies in European ancestry led by the international consortia. The random-effect, inverse-variance weighted MR was employed as the primary method, while MR pleiotropy residual sum and outlier (MR-PRESSO), weighted median, and MR-Egger were implemented as sensitivity tests. All statistical analyses were performed using the R programming language (Version 3.6.1; R Foundation for Statistical Computing, Vienna, Austria). Results Primary MR analysis and replication analysis utilized 5 and 8 instrumental variables, which explained 0.2% and 0.4% variance in physical activity, respectively. In each set, one variant at 17q21 was significantly associated with PD, and MR sensitivity analyses indicated them it as an outlier and source of heterogeneity and pleiotropy. Primary results with the removal of outlier variants suggested odds ratios (ORs) of neurodegenerative diseases per unit increase in objectively measured physical activity were 1.52 for AD (95% confidence interval (95%CI): 0.88–2.63, p = 0.13) and 3.35 for PD (95%CI: 1.32–8.48, p = 0.01), while inconsistent results were shown in the replication set for AD (OR = 1.06, 95%CI: 1.01–1.12, p = 0.02) and PD (OR = 0.99, 95%CI: 0.88–0.12, p = 0.97). Similarly, the beneficial effect of physical activity on ALS (OR = 0.51, 95%CI: 0.29–0.91, p = 0.02) was not confirmed in the replication analysis (OR = 0.96, 95%CI: 0.91–1.02, p = 0.22). Conclusion Genetically predicted physical activity was not robustly associated with risk of neurodegenerative disorders. Triangulating evidence across other studies is necessary in order to elucidate whether enhancing physical activity is an effective approach in preventing the onset of AD, PD, or ALS., Graphical Abstract Image, graphical abstract

DNA methylation age acceleration, the discrepancy between epigenetic age and chronological age, is associated with mortality and chronic diseases, including diabetes, hypertension, and hyperlipidemia. In this study, we investigate whether medications commonly used to treat these diseases in 15 drug categories are associated with four epigenetic age acceleration measures: HorvathAge acceleration (HorvathAA), HannumAge acceleration (HannumAA), PhenoAge acceleration, and GrimAge acceleration (GrimAA) using cross-sectional (Phase 1, N=1,100) and longitudinal (Phases 1 and 2, N=266) data from African Americans in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. In cross-sectional analyses, the use of calcium channel blockers was associated with 1.27 years lower HannumAA after adjusting for covariates including hypertension (p=0.001). Longitudinal analyses showed that, compared to those who never used antihypertensives, those who started to take antihypertensives after Phase 1 had a 0.97-year decrease in GrimAA (p=0.007). In addition, compared to those who never used NSAID analgesics, those who started to take them after Phase 1 had a 2.61-year increase in HorvathAA (p=0.0005). Our study demonstrates that three commonly used medications are associated with DNAm age acceleration in African Americans and sheds light on the potential epigenetic effects of pharmaceuticals on aging at the cellular level.

Suicidal ideation, suicide attempt (SA) and suicide are significantly heritable phenotypes. However, the extent to which these phenotypes share genetic architecture is unclear. This question is of great relevance to determining key risk factors for suicide, and to alleviate the societal burden of suicidal thoughts and behaviors (STBs). To help address the question of heterogeneity, consortia efforts have recently shifted from a focus on suicide within the context of major psychopathology (e.g. major depressive disorder, schizophrenia) to suicide as an independent entity. Recent molecular studies of suicide risk by members of the Psychiatric Genomics Consortium and the International Suicide Genetics Consortium have identified genome-wide significant loci associated with SA and with suicide death, and have examined these phenotypes within and outside of the context of major psychopathology. This review summarizes important insights from epidemiological and biometrical research on suicide, and discusses key empirical findings from molecular genetic examinations of STBs. Polygenic risk scores for these phenotypes have been observed to be associated with case−control status and other risk phenotypes. In addition, estimated shared genetic covariance with other phenotypes suggests specific medical and psychiatric risks beyond major depressive disorder. Broadly, molecular studies suggest a complexity of suicide etiology that cannot simply be accounted for by depression. Discussion of the state of suicide genetics, a growing field, also includes important ethical and clinical implications of studying the genetic risk of suicide.

BackgroundObsessive-compulsive disorder (OCD) is a psychiatric disorder with multiple symptom dimensions (e.g. contamination, symmetry). OCD clusters in families and decades of twin studies clearly demonstrate an important role for genetics in the etiology of the disorder.MethodsIn this review, we summarize the genetic epidemiology and molecular genetic studies of OCD and obsessive-compulsive symptoms.ResultsOCD is a heritable, polygenic disorder with contributions from both common and rare variants, includingde novodeleterious variations. Multiple studies have provided reliable support for a large additive genetic contribution to liability to OCD, with discrete OCD symptom dimensions having both shared and unique genetic risks. Genome-wide association studies have not produced significant results yet, likely because of small sample sizes, but larger meta-analyses are forthcoming. Both twin and genome-wide studies show that OCD shares genetic risk with its comorbid conditions (e.g. Tourette syndrome and anorexia nervosa).ConclusionsDespite significant efforts to uncover the genetic basis of OCD, the mechanistic understanding of how genetic and environmental risk factors interact and converge at the molecular level to result in OCD's heterogeneous phenotype is still mostly unknown. Future investigations should increase ancestral genetic diversity, explore age and/or sex differences in genetic risk for OCD and expand the study of pharmacogenetics, gene expression, gene × environment interactions and epigenetic mechanisms for OCD.

Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in MDD. Studies of common genetic variation in MDD, driven by large international collaborations such as the Psychiatric Genomics Consortium, have confirmed the highly polygenic nature of the disorder and implicated over 100 genetic risk loci to date. Rare copy number variants associated with MDD risk were also recently identified. The goal of this review is to present a broad picture of our current understanding of the epidemiology, genetic epidemiology, molecular genetics, and gene–environment interplay in MDD. Insights into the impact of genetic factors on the aetiology of this complex disorder hold great promise for improving clinical care.

Human blood cells (HBCs) play essential roles in multiple biological processes but their roles in development of uterine polyps are unknown. Here we implemented a Mendelian randomization (MR) analysis to investigate the effects of 36 HBC traits on endometrial polyps (EPs) and cervical polyps (CPs). The random-effect inverse-variance weighted method was adopted as standard MR analysis and three additional MR methods (MR-Egger, weighted median, and MR-PRESSO) were used for sensitivity analyses. Genetic instruments of HBC traits was extracted from a large genome-wide association study of 173,480 individuals, while data for EPs and CPs were obtained from the UK Biobank. All samples were Europeans. Using genetic variants as instrumental variables, our study found that both eosinophil count (OR 0.85, 95% CI 0.79–0.93, P = 1.06 × 10−4) and eosinophil percentage of white cells (OR 0.84, 95% CI 0.77–0.91, P = 2.43 × 10−5) were associated with decreased risk of EPs. The results were robust in sensitivity analyses and no evidences of horizontal pleiotropy were observed. While we found no significant associations between HBC traits and CPs. Our findings suggested eosinophils might play important roles in the pathogenesis of EPs. Besides, out study provided novel insight into detecting uterine polyps biomarkers using genetic epidemiology approaches.

Background Autosomal recessive axonal neuropathy with neuromyotonia has been linked to loss of functional HINT1. The disease is particularly prevalent in Central and South-East Europe, Turkey and Russia due to the high carrier frequency of the c.110G > C (p.Arg37Pro) founder variant. Results In a cohort of 748 Norwegian patients with suspected peripheral neuropathy, we identified two seemingly unrelated individuals, compound heterozygous for a new variant (c.284G > A, p.Arg95Gln) and the most common pathogenic founder variant (c.110G > C, p.Arg37Pro) in the HINT1 gene. Probands presented with motor greater than sensory neuropathy of various onset, accompanied by muscle stiffness and cramps in the limbs. Furthermore, they displayed non-classical symptoms, including pain in the extremities and signs of central nervous system involvement. Haplotype analysis in both patients revealed a common chromosomal background for p.Arg95Gln; moreover, the variant was identified in Swedish carriers. Functional characterization in HINT1-knockout and patient-derived cellular models, and in HNT1-knockout yeast, suggested that the new variant is deleterious for the function of HINT1 and provided mechanistic insights allowing patient stratification for future treatment strategies. Conclusion Our findings broaden the genetic epidemiology of HINT1-neuropathy and have implications for molecular diagnostics of inherited peripheral neuropathies in Scandinavia.

Primary congenital glaucoma (PCG) is a rare glaucoma type that develops in early infantile period and contributes to an elevated pressure on ocular cavity. Variants in gene are the most encountered in PCG cases. The prevalence of PCG is relatively high among Arabs, however its genetic epidemiology remains understudied. This study aims to systematically identify all reported PCG disease-causing variants in the Arab population and investigate their potential genotype-phenotype correlations. We searched four different databases (PubMed, ScienceDirect, Google Scholar, and Scopus) from the time of inception until July 2020. Broad search terms were used to capture all possible information about the genetic epidemiology of PCG among Arabs. We identified a total of 77 disease-causing variants in 361 patients and 88 families; of these, 33 were unique to Arabs. Sixty-nine variants were identified in the gene, five variants were in the gene and single variants were reported in , and genes. The most common reported variant was the c.182 G > A in the gene. All identified variants were from ten Arab Countries (Saudi Arabia, Kuwait, Oman, Egypt, Morocco, Lebanon, Tunisia, Iraq, Algeria, and Mauritania). We identified 44 shared variants with other ethnicities demonstrated a distinctive genotype-phenotype correlation. Consanguinity was observed in the majority of Arab PCG patients, ranging from 45% to 100%. PCG causing variants were identified in 10 Arab countries, which were mostly detected in the gene. Arab patients with PCG seem to have distinctive genotype-phenotype correlations.

Background: Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear. Objective: To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS. Methods: We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators. Results: Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95% confidence interval (CI) = 1.09–1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95% CI = 0.60–0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95% CI = 0.3%–31.0%). Conclusions: This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.

Over 892 million people in 48 countries are at risk of infection by nematodes that cause lymphatic filariasis. As part of the Global Programme to Eliminate Lymphatic Filariasis, mass drug administration is distributed to communities until surveillance indicates infection rates are below target prevalence thresholds. In some countries, including American Samoa, lymphatic filariasis transmission persists despite years of mass drug administration and/or has resurged after cessation. Nothing is known about the population genetics of Wuchereria bancrofti worms in Polynesia, or whether local transmission is persisting and/or increasing due to inadequate mass drug administration coverage, expansion from residual hotspots, reintroduction from elsewhere, or a combination. We extracted DNA from microfilariae on blood slides collected during prevalence surveys in 2014 and 2016, comprising 31 pools of five microfilariae from 22 persons living in eight villages. We sequenced 1104 bp across three mitochondrial markers (ND4, COI, CYTB). We quantified parasite genetic differentiation using variant calls and estimated haplotypes using principal components analysis, F-statistics, and haplotype networks. Of the variants called, all but eight were shared across the main island of Tutuila, and three of those were from a previously described hotspot village, Fagali’i. Genotypic data did not support population genetic structure among regions or villages in 2016, although differences were observed between worms collected in Fagali’i in 2014 and those from 2016. Because estimated haplotype frequency varied between villages, these statistics suggested genetic differentiation, but were not consistent among villages. Finally, haplotype networks demonstrated American Samoan sequence clusters were related to previously published sequences from Papua New Guinea. These are, to our knowledge, the first reports of W. bancrofti genetic variation in Polynesia. The resurgent parasites circulating on the main island of American Samoa represent a single population. This study is the first step towards investigating how parasite population structure might inform strategies to manage resurgence and elimination of lymphatic filariasis.

Background: Little is known about factors associated with emphysema progression in cigarette smokers. We evaluated factors associated with change in emphysema and forced expiratory volume in 1 second (FEV(1)) in participants with and without chronic obstructive pulmonary disease (COPD). Methods: This retrospective study included individuals participating in the COPD Genetic Epidemiology study who completed the 5-year follow-up, including inspiratory and expiratory computed tomography (CT) and spirometry. All paired CT scans were analyzed using micro-mapping, which classifies individual voxels as emphysema or functional small airway disease (fSAD). Presence and progression of emphysema and FEV(1) were determined based on comparison to nonsmoker values. Logistic regression analyses were used to identify clinical parameters associated with disease progression. Results: A total of 3088 participants were included with a mean ± SD age of 60.7±8.9 years, including 72 nonsmokers. In all Global initiative for chronic Obstructive Lung Disease (GOLD) stages, the presence of emphysema at baseline was associated with emphysema progression (odds ratio [OR]: GOLD 0: 4.32; preserved ratio-impaired spirometry [PRISm]; 5.73; GOLD 1: 5.16; GOLD 2: 5.69; GOLD 3/4: 5.55; all p ≤0.01). If there was no emphysema at baseline, the amount of fSAD at baseline was associated with emphysema progression (OR for 1% increase: GOLD 0: 1.06; PRISm: 1.20; GOLD 1: 1.7; GOLD 3/4: 1.08; all p ≤ 0.03).In 1735 participants without spirometric COPD, progression in emphysema occurred in 105 (6.1%) participants and only 21 (1.2%) had progression in both emphysema and FEV(1). Conclusions: The presence of emphysema is an important predictor of emphysema progression. In patients without emphysema, fSAD is associated with the development of emphysema. In participants without spirometric COPD, emphysema progression occurred independently of FEV(1) decline.

Introduction: Smoking cessation counseling is a central part of the Medicare guidelines for lung cancer screening. With increasing age, many heavy smokers eventually stop smoking, however, factors influencing the decision to stop smoking are poorly understood. We postulated that declining health or physician-diagnosis of a medical condition may be associated with successful smoking cessation. Methods: A total of 4448 current and former smokers in Phase 2 of the COPD Genetic Epidemiology (COPDGene®) study answered a question about reasons for stopping smoking. Participants were classified as successful quitters (n=3345), and unsuccessful quitters (n=1003). Reasons cited for quitting were grouped as: medical diagnoses, social factors, symptoms. Logistic modeling of factors associated with successful quitting were adjusted for age, gender, race, and education. Results: The most common factors cited for a quit attempt by all respondents were medical diagnoses (48%), followed by social factors (47%), and respiratory symptoms (36%). Successful quitters were more likely to be older, male, and non-Hispanic White. An adjusted model found increased age, White race, education beyond high school, and male sex favored successful quitting while the cited medical diagnoses, social factors, and “other” reasons were associated with unsuccessful quitting. Fagerstrom Nicotine Dependence scores were ³ 5 in 54% of the unsuccessful group compared to 45% for successful quitters(p

Why people of the same age show differences in age-related functional decline and whether biological aging can be slowed down through lifestyle changes and therapeutics are active research topics. Molecular tools that predict biological age based on DNA methylation markers, known as epigenetic clocks, are facilitating these efforts. In this issue, Kresovich et al. (Am J Epidemiol. 2021;190(6):984–993) investigated a cohort of non-Hispanic White women, demonstrating positive relationships between adiposity measures and the ticking rate of epigenetic clocks in blood. This commentary emphasizes that integrating molecular and genetic epidemiology approaches is crucial to dissecting the complex relationship between obesity and epigenetic aging. The early-life period is explored as a unique opportunity to gain novel insights into links between developmental processes and aging in later life. Last, the landscape of the next frontier in aging research is described in light of the imperative for transdisciplinary approaches to outline a shared vision and public health implementation dilemmas.

Представлен нозологический спектр моногенных наследственных болезней (МНБ) в трех районах Республики Северная Осетия Алания (РСОА) - Правобережном, Ардонском и Кировском, общей численностью 119 590 человек. Обследовано все население районов по протоколу генетико-эпидемиологических исследований (разработка ФГБНУ «МГНЦ»), выявлено и диагностировано 600 пациентов (из 418 семей) с различными МНБ. Всего выявлено 135 нозологических форм - 65 с аутосомно-доминантным типом наследования (АД), 57 с аутосомно-рецессивным (АР) и 14 с Х-сцепленным (Х-сц.). Определены распространенность заболеваний, частые и редкие нозологические формы. Проведено сравнение нозологического спектра и распространенности отдельных МНБ с таковыми в ранее обследованных популяциях европейской части России. Выявлены особенности разнообразия МНБ. Более высокие значения распространенности, чем в других популяциях РФ выявлены синдром Элерса-Данло, миотоническая дистрофия, несиндромальная умственная отсталость с различными типами наследования, различные формы пигментного ретинита и др. Ряд заболеваний, частых в обследованных регионах РФ, наоборот, встречались реже - вульгарный ихтиоз, нейрофиброматоз, наследственная моторно-сенсорная нейропатия и ихтиозиформная эритродеремия. In this article we present the nosological spectrum of monogenic hereditary diseases (MHD) in three districts of the Republic of North Ossetia - Alania (RNOA) - Pravoberezhny, Ardonsky and Kirovsky, with a total population of 119,590 people. The entire population of the districts was examined according to the Protocol of genetic and epidemiological studies (developed by the Federal state budgetary Research Centre for Medical Genetics), 600 patients (from 418 families) with various NBS were identified and diagnosed. We identified 136 nosological forms of MHD - 65 with autosomal dominant type of inheritance (AD), 57 with autosomal recessive (AR) and 14 with X-linked (X-lin.). We determine the prevalence of diseases, frequent and rare nosological forms. The nosological spectrum and prevalence of individual MHD were compared with previously surveyed populations in the European part of Russia: Kirov, Kostroma, Arkhangelsk, Tver, Bryansk, Rostov regions, Krasnodar territory and the Republics of Karachay-Cherkessia, Adygea, Tatarstan, Bashkortostan, Mari El, Udmurtia and Chuvashia. Features of the MHD diversity are revealed. With higher prevalence values than in other populations of the Russian Federation, Ehlers-Danlo syndrome, myotonic dystrophy, non - syndromic mental retardation with various types of inheritance and various forms of retinitis pigmentosa, etc. A number of diseases that are frequent in the Russian Federation have shown on the contrary lower prevalence values - vulgar ichthyosis, neurofibromatosis, hereditary motor-sensory neuropathy and ichthyosiform erythroderemia.

In the absence of contemporary, population-based epidemiological studies, estimates of the incidence and prevalence of the inherited cardiomyopathies have been derived from screening studies, most often of young adult populations, to assess cardiovascular risk or to detect the presence of disease in athletes or military recruits. The global estimates for hypertrophic cardiomyopathy (1/500 individuals), dilated cardiomyopathy (1/250) and arrhythmogenic right ventricular cardiomyopathy (1/5,000) are probably conservative given that only individuals who fulfil diagnostic criteria would have been included. This caveat is highly relevant because a substantial minority or even a majority of individuals who carry disease-causing genetic variants and are at risk of disease complications have incomplete and/or late-onset disease expression. The genetic literature on cardiomyopathy, which is often focused on the identification of genetic variants, has been biased in favour of pedigrees with higher penetrance. In clinical practice, an abnormal electrocardiogram with normal or non-diagnostic imaging results is a common finding for the sarcomere variants that cause hypertrophic cardiomyopathy, the titin and sarcomere variants that cause dilated cardiomyopathy and the desmosomal variants that cause either arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy. Therefore, defining the genetic epidemiology is also challenging given the overlapping phenotypes, incomplete and age-related expression, and highly variable penetrance even within individual families carrying the same genetic variant.

It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.

We specify a mathematical model of Hypertrophic Cardiomyopathy (HCM) and consider the potential costs arising from adverse selection in a life insurance market. HCM is a dominantly inherited heart ...

Background Hypertensive diseases in pregnancy have been associated with altered cardiac structure and function, yet these associations have not been systematically investigated in larger populations including African Americans. We evaluated the relationships between hypertensive diseases in pregnancy with cardiac structure and function later in life in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Methods We investigated 1013 African American women sibships with echocardiographic measurements from the GENOA study (Phase II, 2000-05; Jackson, MS). Women were classified as self-reported nulliparous (n = 61), a history of normotensive pregnancies (n = 780), a history of a hypertensive pregnancies (n = 152), or a history of preeclampsia (n = 20). We compared adjusted associations among these 4 groups with echocardiographic measurements of cardiac structure and function using generalized estimating equations, accounting for familial clustering. Results Among 1013 women with echocardiographic data (mean age 62 ± 9.5 years), women with a history of hypertensive pregnancy had lower left ventricular ejection fraction (LVEF) (P = 0.043) compared to nulliparous women and higher left atrial systolic dimension (LASD) compared to women with a history of normotensive pregnancies (P = 0.010), After adjusting for cardiovascular risk factors. There were no statistically significant differences in other echocardiographic parameters among these groups. Conclusions A history of hypertension in pregnancy is associated with lower LVEF later in life, compared to nulliparous women and higher LASD compared to women with a history of normotensive pregnancies. However, given the multiple comparisons considered, this finding should be interpreted cautiously and requires further study.

Lipoprotein(a) is an atherogenic low-density lipoprotein-like particle and circulating levels are largely determined by genetics. Patients with familial hypercholesterolemia (FH) have elevated lipoprotein(a); however, it remains unclear why.This study compared the levels of lipoprotein(a) and associated genetic factors between individuals that were ascertained for FH clinically versus genetically.We investigated causes of elevated lipoprotein(a) in individuals with clinically diagnosed FH (FH cohort, n = 391) and in individuals with genetically diagnosed FH from the general population (UK Biobank; n = 37,486).Patients in the FH cohort had significantly greater lipoprotein(a) levels than either the general population or non-FH dyslipidemic patients. This was accounted for by increased frequency of the rs10455872-G LPA risk allele (15.1% vs. 8.8%; p 0.05). However, within the FH cohort, lipoprotein(a) levels did not differ based on the presence or absence of an FH-causing variant (means = 1.43 log mg/dl vs. 1.42 log mg/dl; p = 0.97). Lipoprotein(a) levels were also not statistically different between individuals with and without an FH-causing variant in the UK Biobank cohort, which represents a population sample not biased to cardiovascular ascertainment (n = 221 vs. 37,486). We performed a phenome-wide association study between LPA genotypes and 19,202 phenotypes to demonstrate that elevated lipoprotein(a) is associated with increased low-density lipoprotein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of FH.These results suggest that FH does not cause elevated lipoprotein(a), but that elevated lipoprotein(a) increases the likelihood that an individual with genetic FH will be clinically recognized.

Congruent, low-friction relative movement between the articulating elements of a synovial joint is an essential pre-requisite for sustained, efficient, function. Where disorders of joint formation or maintenance exist, mechanical overloading and osteoarthritis (OA) follow. The heritable component of OA accounts for ~ 50% of susceptible risk. Although almost 100 genetic risk loci for OA have now been identified, and the epidemiological relationship between joint development, joint shape and osteoarthritis is well established, we still have only a limited understanding of the contribution that genetic variation makes to joint shape and how this modulates OA risk. In this article, a brief overview of synovial joint development and its genetic regulation is followed by a review of current knowledge on the genetic epidemiology of established joint shape disorders and common shape variation. A summary of current genetic epidemiology of OA is also given, together with current evidence on the genetic overlap between shape variation and OA. Finally, the established genetic risk loci for both joint shape and osteoarthritis are discussed.

COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly population. To accelerate the understanding of the genetics of AMD, we conducted a meta-analysis of genome-wide association studies (GWAS) combining data from the International AMD Genomics Consortium AMD-2016 GWAS (16,144 advanced AMD cases and 17,832 controls), AMD-2013 GWAS (17,181 cases and 60,074 controls), and new data on 4017 AMD cases and 14,984 controls from Genetic Epidemiology Research on Aging study. We identified 12 novel AMD loci near or within C4BPA-CD55, ZNF385B, ZBTB38, NFKB1, LINC00461, ADAM19, CPN1, ACSL5, CSK, RLBP1, CLUL1, and LBP. We then replicated the associations of the novel loci in independent cohorts, UK Biobank (5860 cases and 126,726 controls) and FinnGen (1266 cases and 47,560 control). In general, the concordance in effect sizes was very high (correlation in effect size estimates 0.89), 11 of 12 novel loci were in the expected direction, 5 were associated with AMD at a nominal significance level, and rs3825991 (near gene RLBP1) after Bonferroni correction. We identified an additional 21 novel genes using a gene-based test. Most of the novel genes are expressed in retinal tissue and could be involved in the pathogenesis of AMD (i.e., complement, inflammation, and lipid pathways). These findings enhance our understanding of the genetic architecture of AMD and shed light on the biological process underlying AMD pathogenesis.

Objective: A number of epidemiological studies have reported that decreased serum bilirubin, an endogenous antioxidant, is associated with cardiovascular disease. However, previous Mendelian randomization analyses conducted using a single sample have shown no evidence of association. Approach and Results: A 2-sample summary Mendelian randomization study was performed by obtaining exposure and outcome data from separate nonoverlapping samples. We utilized data from the KoGES (Korean Genome and Epidemiology Study; n=25 406) and KCPS-II (Korean Cancer Prevention Study-II; n=14 541) biobank for serum bilirubin and stroke, respectively. Using KoGES, a total of 1784 single nucleotide polymorphisms associated with serum bilirubin levels were discovered using a genome-wide significance threshold ( P −8 ), of which 10 single nucleotide polymorphisms were identified as independent ( R 2 P =0.046). This association increased in magnitude when restricting the analysis to ischemic stroke cases (odds ratio, 0.302 [95% CI, 0.105–0.868]; P =0.026). Conclusions: Our findings provide evidence of significant causal relationship between high levels of bilirubin and decreased stroke risk in Korean population in agreement with observational approaches. This highlights the potential for bilirubin to serve as a therapeutic target for oxidative stress-related diseases such as stroke and suggests that previous findings were not a consequence of unmeasured confounding.

Background: High disease burden suggests the desirability to identify high-risk Asian never-smoking females (NSF) who may benefit from low-dose CT (LDCT) screening. In North America, one is eligible for LDCT screening if one satisfies the U.S. Preventive Services Task Force (USPSTF) criteria or has model-estimated 6-year risk greater than 0.0151. According to two U.S. reports, only 36.6% female patients with lung cancer met the USPSTF criteria, while 38% of the ever-smokers ages 55 to 74 years met the USPSTF criteria. Methods: Using data on NSFs in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma and the Taiwan Biobank before August 2016, we formed an age-matched case–control study consisting of 1,748 patients with lung cancer and 6,535 controls. Using these and an estimated age-specific lung cancer 6-year incidence rate among Taiwanese NSFs, we developed the Taiwanese NSF Lung Cancer Risk Models using genetic information and simplified questionnaire (TNSF-SQ). Performance evaluation was based on the newer independent datasets: Taiwan Lung Cancer Pharmacogenomics Study (LCPG) and Taiwan Biobank data after August 2016 (TWB2). Results: The AUC based on the NSFs ages 55 to 70 years in LCPG and TWB2 was 0.714 [95% confidence intervals (CI), 0.660–0.768]. For women in TWB2 ages 55 to 70 years, 3.94% (95% CI, 2.95–5.13) had risk higher than 0.0151. For women in LCPG ages 55 to 74 years, 27.03% (95% CI, 19.04–36.28) had risk higher than 0.0151. Conclusions: TNSF-SQ demonstrated good discriminative power. The ability to identify 27.03% of high-risk Asian NSFs ages 55 to 74 years deserves attention. Impact: TNSF-SQ seems potentially useful in selecting Asian NSFs for LDCT screening.

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC 1

Graphical abstract, ATP7A is a critical copper transporter involved in Menkes Disease, Occipital horn Syndrome and X-linked distal spinal muscular atrophy type 3 which are X linked genetic disorders. These are rare diseases and their genetic epidemiology of the diseases is unknown. A number of genetic variants in the genes have been reported in published literature as well as databases, however, understanding the pathogenicity of variants and genetic epidemiology requires the data to be compiled in a unified format. To this end, we systematically compiled genetic variants from published literature and datasets. Each of the variants were systematically evaluated for evidences with respect to their pathogenicity and classified as per the American College of Medical Genetics and the Association of Molecular Pathologists (ACMG-AMP) guidelines into Pathogenic, Likely Pathogenic, Benign, Likely Benign and Variants of Uncertain Significance. Additional integrative analysis of population genomic datasets provides insights into the genetic epidemiology of the disease through estimation of carrier frequencies in global populations. To deliver a mechanistic explanation for the pathogenicity of selected variants, we also performed molecular modeling studies. Our modeling studies concluded that the small structural distortions observed in the local structures of the protein may lead to the destabilization of the global structure. To the best of our knowledge, ATP7A Clinical Genetics Resource is one of the most comprehensive compendium of variants in the gene providing clinically relevant annotations in gene.

Increasing evidence indicates that specific genetic variants influence the severity of outcomes after infection with COVID-19. However, it is not clear whether the effect of these genetic factors is independent of the risk due to more established non-genetic demographic and metabolic risk factors such as male sex, poor cardiometabolic health, and low socioeconomic status. We sought to identify interactions between genetic variants and non-genetic risk factors influencing COVID-19 severity via a genome-wide interaction study in the UK Biobank. Of 378,051 unrelated individuals of European ancestry, 2,402 were classified as having experienced severe COVID-19, defined as hospitalization or death due to COVID-19. Exposures included sex, cardiometabolic risk factors (obesity and type 2 diabetes [T2D], tested jointly), and multiple deprivation index. Multiplicative interaction was tested using a logistic regression model, conducting both an interaction test and a joint test of genetic main and interaction effects. Five independent variants reached genome-wide significance in the joint test, one of which also reached significance in the interaction test. One of these, rs2268616 in the PGF gene, showed stronger effects in males and in individuals with T2D. None of the five variants showed effects on a similarly-defined phenotype in a lookup in the COVID-19 Host Genetics Initiative. These results reveal potential additional genetic loci contributing to COVID-19 severity and demonstrate the value of including non-genetic risk factors in an interaction testing approach for genetic discovery.

Background Multiple acyl-CoA dehydrogenase deficiency (MADD) is a riboflavin-responsive lipid-storage myopathy caused by mutations in the EFTA, EFTB or ETFDH genes. We report a Chinese family of Southern Min origin with two affected siblings with late-onset riboflavin-responsive MADD due to a homozygous c.250G > A EFTDH mutation and review the genetic epidemiology of the c.250G > A mutation. Case presentation Both siblings presented with exercise-induced myalgia, progressive proximal muscle weakness and high levels of serum muscle enzymes and were initially diagnosed as polymyositis after a muscle biopsy. A repeat biopsy in one sibling subsequently showed features of lipid storage myopathy and genetic analysis identified a homozygous mutation (c.250G > A) in the ETFDH gene in both siblings and carriage of the same mutation by both parents. Glucocorticoid therapy led to improvement in muscle enzyme levels, but little change in muscle symptoms, and only after treatment with riboflavin was there marked improvement in exercise tolerance and muscle strength. The frequency and geographic distribution of the c.250G > A mutation were determined from a literature search for all previously reported cases of MADD with documented mutations. Our study found the c.250G > A mutation is the most common EFTDH mutation in riboflavin-responsive MADD (RR-MADD) and is most prevalent in China and South-East Asia where its epidemiology correlates with the distribution and migration patterns of the southern Min population in Southern China and neighbouring countries. Conclusions Mutations in ETFDH should be screened for in individuals with lipid-storage myopathy to identify patients who are responsive to riboflavin. The c.250G > A mutation should be suspected particularly in individuals of southern Min Chinese background.

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

BackgroundPrevious studies have suggested essential roles of growth factors on the risk of Multiple Sclerosis (MS), but it remains undefined whether the effects are causal.ObjectiveWe applied Mendelian randomization (MR) approaches to disentangle the causal relationship between genetically predicted circulating levels of growth factors and the risk of MS.MethodsGenetic instrumental variables for fibroblast growth factor (FGF) 23, growth differentiation factor 15 (GDF15), insulin growth factor 1 (IGF1), insulin-like growth factor binding proteins 3 (IGFBP3) and vascular endothelial growth factor (VEGF) were obtained from up-to-date genome-wide association studies (GWAS). Summary-level statistics of MS were obtained from the International Multiple Sclerosis Genetics Consortium, incorporating 14,802 subjects with MS and 26,703 healthy controls of European ancestry. Inverse-variance weighted (IVW) MR was used as the primary method and multiple sensitivity analyses were employed in this study.ResultsGenetically predicted circulating levels of FGF23 were associated with risk of MS. The odds ratio (OR) of IVW was 0.63 (95% confidence interval [CI], 0.49–0.82; p < 0.001) per one standard deviation increase in circulating FGF23 levels. Weighted median estimators also suggested FGF23 associated with lower MS risk (OR = 0.67; 95% CI, 0.51-0.87; p = 0.003). While MR-Egger approach provided no evidence of horizontal pleiotropy (intercept = -0.003, p = 0.95). Results of IVW methods provided no evidence for causal roles of GDF1, IGF1, IGFBP3 and VEGF on MS risks, and additional sensitivity analyses confirmed the robustness of these null findings.ConclusionOur results implied a causal relationship between FGF23 and the risk of MS. Further studies are warranted to confirm FGF23 as a genetically valid target for MS.

Purpose: Hyperopia (farsightedness) has been associated with a deficit in children's educational attainment in some studies. We aimed to investigate the causality of the relationship between refractive error and educational attainment.Methods: Mendelian randomization (MR) analysis in 74,463 UK Biobank participants was used to estimate the causal effect of refractive error on years spent in full-time education, which was taken as a measure of educational attainment. A polygenic score for refractive error derived from 129 genetic variants was used as the instrumental variable. Both linear and nonlinear (allowing for a nonlinear relationship between refractive error and educational attainment) MR analyses were performed.Results: Assuming a linear relationship between refractive error and educational attainment, the causal effect of refractive error on years spent in full-time education was estimated as -0.01 yr/D (95% confidence interval, -0.04 to +0.02; P = 0.52), suggesting minimal evidence for a non-zero causal effect. Nonlinear MR supported the hypothesis of the nonlinearity of the relationship (I2 = 80.3%; Cochran's Q = 28.2; P = 8.8e-05) but did not suggest that hyperopia was associated with a major deficit in years spent in education.Conclusions: This work suggested that the causal relationship between refractive error and educational attainment was nonlinear but found no evidence that moderate hyperopia caused a major deficit in educational attainment. Importantly, however, because statistical power was limited and some participants with moderate hyperopia would have worn spectacles as children, modest adverse effects may have gone undetected.Translational Relevance: These findings suggest that moderate hyperopia does not cause a major deficit in educational attainment.

Background: This study examined the differences in the prevalence and clinical features of asthma–chronic obstructive pulmonary disease (COPD) overlap (ACO) with identical diagnostic criteria by race and ethnicity in two nationwide cohorts of COPD.Methods: We used data from the Korean COPD Subgroup Study (KOCOSS) and phase I of the US Genetic Epidemiology of COPD (COPDGene) study. We defined ACO by satisfying bronchodilator response (BDR) >15% and 400 ml and/or blood eosinophil count ≥300/μl.Results: The prevalences of ACO according to ethnicity were non-Hispanic white (NHW), 21.4%; African American (AA), 17.4%; and Asian, 23.8%. Asian patients with ACO were older, predominantly male, with fewer symptoms, more severe airflow limitation, and fewer comorbidities than NHW and AA patients. During 1-year follow-up, exacerbations occurred in 28.2, 22.0, and 48.4% of NHW, AA, and Asian patients with ACO, respectively. Compared to patients with non-ACO from the same racial group, the risk for exacerbation was significantly higher in NHW and Asian patients with ACO [adjusted incident rate ratio (aIRR), 1.17; 95% CI, 1.01–1.36, and aIRR, 1.37; 95% CI, 1.09–1.71 for NHW and Asian patients with ACO, respectively]. Inhaled corticosteroid (ICS) reduced the risk for future exacerbation in total patients with ACO but the effect was not significant in each racial group.Conclusions: The prevalence of ACO was similar in the two cohorts using the same diagnostic criteria. The risk for future exacerbation was significantly higher in ACO, and the use of ICS reduced the risk for exacerbation in total patients with ACO.

Background Obesity is associated with long‐term health consequences including cardiovascular disease. Separating the independent effects of childhood and adulthood obesity on cardiovascular disease risk is challenging as children with obesity typically remain overweight throughout the lifecourse. Methods and Results This study used 2‐sample univariable and multivariable Mendelian randomization to estimate the effect of childhood body size both independently and after accounting for adult body size on 12 endpoints across the cardiovascular disease disease spectrum. Univariable analyses identified strong evidence of a total effect between genetically predicted childhood body size and increased risk of atherosclerosis, atrial fibrillation, coronary artery disease, heart failure, hypertension, myocardial infarction, peripheral artery disease, and varicose veins. However, evidence of a direct effect was weak after accounting for adult body size using multivariable Mendelian randomization, suggesting that childhood body size indirectly increases risk of these 8 disease outcomes via the pathway involving adult body size. Conclusions These findings suggest that the effect of genetically predicted childhood body size on the cardiovascular disease outcomes analyzed in this study are a result of larger body size persisting into adulthood. Further research is necessary to ascertain the critical timepoints where, if ever, the detrimental impact of obesity initiated in early life begins to become immutable.

Yuanlong Hu,1,&ast; Xiaomeng Cheng,1,&ast; Zhanjun Qiu,2 Xianhai Chen2 1Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 2The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhanjun Qiu; Xianhai Chen Email qiuzhj227@163.com; chenxianhai18@163.comPurpose: This study aimed to identify the COPD molecular subtypes reflecting pulmonary function damage on the basis of metabolism-related gene expression, which provided the opportunity to study the metabolic heterogeneity and the association of metabolic pathways with pulmonary function damage.Methods: Univariate linear regression and the Boruta algorithm were used to select metabolism-related genes associated with forced expiratory volume in the first second (FEV1) and FEV1/forced vital capacity (FVC) in the Evaluation of COPD to Longitudinally Identify Predictive Surrogate Endpoints (ECLIPSE) cohort. COPD subtypes were further identified by consensus clustering with best-fit. Then, we analyzed the differences in the clinical characteristics, metabolic pathways, immune cell characteristics, and transcription features among the subtypes.Results: This study identified two subtypes (C1 and C2). C1 exhibited higher levels of lower pulmonary function and innate immunity than C2. Ten metabolic pathways were confirmed as key metabolic pathways. The pathways related to N-glycan, hexosamine, purine, alanine, aspartate and glutamate tended to be positively associated with the abundance of adaptive immune cells and negatively associated with the abundance of innate immune cells. In addition, other pathways had opposite trends. All results were verified in Genetic Epidemiology of COPD (COPDGene) datasets.Conclusion: The two subtypes reflect the pulmonary function damage and help to further understand the metabolic mechanism of pulmonary function in COPD. Further studies are needed to prove the prognostic and therapeutic value of the subtypes.Keywords: chronic obstructive pulmonary disease, molecular subtype, metabolic pathway, pulmonary function

BackgroundPrevious observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).MethodsUsing summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated (p < 5 × 10–8) with GDF-15 were selected as instrumental variables (n = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR–Egger, leave-one-out analysis, and Cochran’s Q-test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages.ResultsMR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04–1.24; p = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 (p = 0.450). The causal effects of GDF-15 on PD (p = 0.597) or ALS (p = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses.ConclusionWe highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target.

FMR1 CGG repeat length was assayed in 5499 research participants (2637 men and 2862 women) in the Wisconsin Longitudinal Study (WLS), a population-based cohort. Most past research has focused on clinically-ascertained individuals with expansions in CGG repeats, either those with fragile X syndrome (> 200 CGG repeats), the FMR1 premutation (55–200 repeats), or in the gray zone (variously defined as 45–54 or 41–54 repeats). In contrast, the WLS is a unique source of data that was obtained from an unselected cohort of individuals from the general population for whom FMR1 CGG repeat length was assayed. The WLS is a random sample of one-third of all high school seniors in the state of Wisconsin in 1957. The most recent round of data collection was in 2011; thus, the study spanned over 50 years. Saliva samples were obtained from 69% of surviving members of the cohort in 2008 and 2011, from which CGG repeats were assayed. With one exception, the CGG repeat length of all members of this cohort was below 100 (ranging from 7 to 84). The present study evaluated the genotype-phenotype associations of CGG repeat number and IQ, college graduation, age at menopause, number of biological children, having a child with intellectual or developmental disabilities, and the likelihood of experiencing an episode of depression during adulthood. Linear and curvilinear effects were probed. Although effect sizes were small, significant associations were found between CGG repeat length and high school IQ score, college graduation, number of biological children, age at menopause, and the likelihood of having an episode of depression. However, there was no significant association between repeat length and having a child diagnosed with an IDD condition. This study demonstrates a continuum of phenotype effects with FMR1 repeat lengths and illustrates how research inspired by a rare genetic condition (such as fragile X syndrome) can be used to probe genotype-phenotype associations in the general population.

We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.

There is an abundance of malaria genetic data being collected from the field, yet using these data to understand the drivers of regional epidemiology remains a challenge. A key issue is the lack of models that relate parasite genetic diversity to epidemiological parameters. Classical models in population genetics characterize changes in genetic diversity in relation to demographic parameters, but fail to account for the unique features of the malaria life cycle. In contrast, epidemiological models, such as the Ross-Macdonald model, capture malaria transmission dynamics but do not consider genetics. Here, we have developed an integrated model encompassing both parasite evolution and regional epidemiology. We achieve this by combining the Ross-Macdonald model with an intra-host continuous-time Moran model, thus explicitly representing the evolution of individual parasite genomes in a traditional epidemiological framework. Implemented as a stochastic simulation, we use the model to explore relationships between measures of parasite genetic diversity and parasite prevalence, a widely-used metric of transmission intensity. First, we explore how varying parasite prevalence influences genetic diversity at equilibrium. We find that multiple genetic diversity statistics are correlated with prevalence, but the strength of the relationships depends on whether variation in prevalence is driven by host- or vector-related factors. Next, we assess the responsiveness of a variety of statistics to malaria control interventions, finding that those related to mixed infections respond quickly (∼months) whereas other statistics, such as nucleotide diversity, may take decades to respond. These findings provide insights into the opportunities and challenges associated with using genetic data to monitor malaria epidemiology., Author Summary Knowledge of how the prevalence of P.falciparum malaria varies, either between regions or through time, is critical to the operation of malaria control programs. Yet obtaining this information through traditional methods presents many challenges. Parasite genetic data is increasingly accessible, and may provide an alternative means to estimate P.falciparum prevalence in the field. However, our understanding of how the genetic diversity of parasite populations relates to prevalence is limited, and suitable models to guide our understanding are largely lacking. Here, we merge two classical models—the Ross-Macondald and the Moran—to produce a framework in which the relationships between parasite genetic diversity and prevalence can be explored. We find that several genetic diversity statistics are correlated with prevalence, although to differing degrees, and over different time scales. Overall, statistics related to mixed infection are robustly and rapidly responsive to changes in prevalence, suggesting they may be a useful focal point for the development of malaria surveillance methods that harness genetic data.

The Mayan population of Guatemala is understudied within eye and vision research. Studying an observational homogenous, geographically isolated population of individuals seeking eye care may identify unique clinical, demographic, environmental and genetic risk factors for blinding eye disease that can inform targeted and effective screening strategies to achieve better and improved health care distribution. This study served to: (a) identify the ocular health needs within this population, and (b) identify any possible modifiable risk factors contributing to disease pathophysiology within this population. We conducted a cross-sectional study with 126 participants. Each participant completed a comprehensive eye examination, provided a blood sample for genetic analysis, and received a structured core baseline interview for a standardized epidemiological questionnaire at the Salama Lions Club Eye Hospital in Salama, Guatemala. Interpreters were available for translation to the patients’ native dialect, to assist participants during their visit. We performed a genome-wide association study for ocular disease association on the blood samples using Illumina’s HumanOmni2.5-8 chip to examine single nucleotide polymorphism SNPs in this population. After implementing quality control measures, we performed adjusted logistic regression analysis to determine which genetic and epidemiological factors were associated with eye disease. We found that the most prevalent eye conditions were cataracts (54.8%) followed by pseudoexfoliation syndrome (PXF) (24.6%). The population with both conditions was 22.2%. In our epidemiological analysis, we found that eye disease was significantly associated with advanced age. Cataracts were significantly more common among those living in the 10 districts with the least resources. Furthermore, having cataracts was associated with a greater likelihood of PXF after adjusting for both age and sex. In our genetic analysis, the SNP most nominally significantly associated with PXF lay within the gene KSR2 (p &lt, 1 × 10−5). Several SNPs were associated with cataracts at genome-wide significance after adjusting for covariates (p &lt, 5 × 10−8). About seventy five percent of the 33 cataract-associated SNPs lie within 13 genes, with the majority of genes having only one significant SNP (5 × 10−8). Using bioinformatic tools including PhenGenI, the Ensembl genome browser and literature review, these SNPs and genes have not previously been associated with PXF or cataracts, separately or in combination. This study can aid in understanding the prevalence of eye conditions in this population to better help inform public health planning and the delivery of quality, accessible, and relevant health and preventative care within Salama, Guatemala.

Etiological studies have shown genetic disorders to be a major cause of sensorineural hearing loss, but there are a limited number of comprehensive etiological reports based on genetic analysis. In the present study, the same platform using a diagnostic DNA panel carrying 63 deafness genes and the same filtering algorithm were applied to 10,047 samples obtained from social health insurance-based genetic testing of hearing loss. The most remarkable result obtained in this comprehensive study was that the data first clarified the genetic epidemiology from congenital/early-onset deafness to late-onset hearing loss. The overall diagnostic rate was 38.8%, with the rate differing for each age group; 48.6% for the congenital/early-onset group (~5y.o.), 33.5% for the juvenile/young adult-onset group, and 18.0% for the 40+ y.o. group. Interestingly, each group showed a different kind of causative gene. With regard to the mutational spectra, there are certain recurrent variants that may be due to founder effects or hot spots. A series of haplotype studies have shown many recurrent variants are due to founder effects, which is compatible with human migration. It should be noted that, regardless of differences in the mutational spectrum, the clinical characteristics caused by particular genes can be considered universal. This comprehensive review clarified the detailed clinical characteristics (onset age, severity, progressiveness, etc.) of hearing loss caused by each gene, and will provide useful information for future clinical application, including genetic counseling and selection of appropriate interventions.