Insights into hair dye use and self-reported adverse skin reactions in the Dutch general population: A cross-sectional questionnaire-based study.

BACKGROUND: Hair dyes are widely used in daily life. However, data on self-reported adverse skin reactions are scarce. OBJECTIVES: To estimate the proportion of lifetime hair dye use and self-reported adverse skin reactions in the Dutch general population, and to investigate the association between (adverse skin reactions to) hair dye use and contact allergy-related factors. METHODS: This cross-sectional study collected questionnaire-derived data from the Lifelines cohort. Logistic regression analyses were conducted between (adverse skin reactions to) hair dye use and black henna tattoo use, reactions to henna tattoos, patch testing, hand eczema and an occupation as hairdresser or beautician. RESULTS: The proportion of hair dye use was 63.1% of 70 987 participants, of which 6.8% experienced adverse skin reactions, mostly mild (77.7%). Hair dye users and those with skin reactions were both positively associated (p < 0.05) with female sex, middle-age, (positive) patch test results and hairdresser or beautician occupations. Hair dye users were more likely to have had henna tattoos, and those with reactions to hair dye were more likely to have had reactions to henna tattoos. CONCLUSIONS: Hair dye use is prevalent among the Dutch general population and frequently causes adverse skin reactions, especially in females who had black henna tattoos.

A Large-Scale Genome-Wide Gene-Sleep Interaction Study in 732,564 Participants Identifies Lipid Loci Explaining Sleep-Associated Lipid Disturbances.

We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify novel genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. We collected data from 55 cohorts with a combined sample size of 732,564 participants (87% European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20% of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for the one-degree of freedom tests of interaction and two-degree of freedom joint tests of the main and interaction effect. In the cross-population meta-analyses, the one-degree of freedom variant-sleep interaction test identified 10 loci (P int <5.0e-9) not previously observed for lipids. Of interest, the ASPH locus (TG, LTST) is a target for aspartic and succinic acid metabolism previously shown to improve sleep and cardiovascular risk. The two-degree of freedom analyses identified an additional 7 loci that showed evidence for variant-sleep interaction (P joint <5.0e-9 in combination with P int <6.6e-6). Of these, the SLC8A1 locus (TG, STST) has been considered a potential treatment target for reduction of ischemic damage after acute myocardial infarction. Collectively, the 17 (9 with STST; 8 with LTST) loci identified in this large-scale initiative provides evidence into the biomolecular mechanisms underpinning sleep-duration-associated changes in lipid levels. The identified druggable targets may contribute to the development of novel therapies for dyslipidemia in people with sleep disturbances.

Role of Inflammation in Depressive and Anxiety Disorders, Affect, and Cognition: Genetic and Non-Genetic Findings in the Lifelines Cohort Study.

Inflammation is associated with a range of neuropsychiatric symptoms; however, the nature of the causal relationship is unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognition. We tested in ≈ 55,098 (59% female) individuals from the Dutch Lifelines cohort the concurrent/prospective associations of C-reactive protein (CRP) with: depressive and anxiety disorders; positive/negative affect; and attention, psychomotor speed, episodic memory, and executive functioning. Additionally, we examined the association between inflammatory GRSs (CRP, interleukin-6 [IL-6], IL-6 receptor [IL-6R and soluble IL-6R (sIL-6R)], glycoprotein acetyls [GlycA]) on these same outcomes (Nmax=57,946), followed by MR analysis examining evidence of causality of CRP on outcomes (Nmax=23,268). In non-genetic analyses, higher CRP was associated with a depressive disorder, lower positive/higher negative affect, and worse executive function, attention, and psychomotor speed after adjusting for potential confounders. In genetic analyses, CRPgrs was associated with any anxiety disorder (ß = 0.002, p = 0.037) whereas GlycAGRS was associated with major depressive disorder (ß = 0.001, p = 0.036). Both CRPgrs (ß = 0.006, p = 0.035) and GlycAGRS (ß = 0.006, p = 0.049) were associated with greater negative affect. Inflammatory GRSs were not associated with cognition, except slL-6RGRS which was associated with poorer memory (ß=-0.009, p = 0.018). There was weak evidence for a CRP-anxiety association using MR (ß = 0.12; p = 0.054). Genetic and non-genetic analyses provide consistent evidence for an association between CRP and negative affect. These results suggest that dysregulated immune physiology may impact a broad range of trans-diagnostic affective symptoms.

Genome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants.

BACKGROUND: Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome-wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. METHODS AND RESULTS: We performed genome-wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2-stage analysis (genome-wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single-stage genome-wide meta-analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2-degrees of freedom joint main and interaction and 1-degree of freedom interaction P values. In 2-stage and single-stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2-degrees of freedom joint main and interaction P value <5×10-8). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single-stage meta-analysis were not reported previously (SPPL2B and RFX6). CONCLUSIONS: We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.

A genome-wide association study of hand eczema identifies locus 20q13.33 and reveals genetic overlap with atopic dermatitis.

BACKGROUND: Twin studies revealed that genetic effects play a role in hand eczema (HE), but the responsible genetic factors are unknown. OBJECTIVES: To identify and characterise genetic loci associated with HE and to provide insight into the genetic overlap between HE and atopic dermatitis (AD). METHODS: We used questionnaire-derived and genotype data from the European population-based Lifelines cohort and biobank. We performed a discovery genome-wide association study (GWAS) of HE (2879 cases and 16 249 controls) and of AD (1706 cases and 17 190 controls). We replicated our findings in an independent Lifelines sample for HE (1188 cases and 6431 controls) and AD (757 cases and 6747 controls). We conducted several post-GWAS analyses and performed genetic correlation analyses between our HE results and independent AD data. RESULTS: The two-step GWAS of HE, regardless of adjusting for AD, identified one independent locus 20q13.33, likely driven by a number of causal single-nucleotide polymorphisms. For the AD GWAS, we replicated a known stop-gained rs61816761 at locus 1q21.3 (FLG, FLGAS1). We found a strong genetic correlation (p < 0.01) between HE and AD (rg = 0.65), regardless of adjusting for AD (rg = 0.63). CONCLUSIONS: Locus 20q13.33 is associated with HE, and there is a large genetic overlap between HE and AD.

Role of Inflammation in Depressive and Anxiety Disorders, Affect, and Cognition: Genetic and Non-Genetic Findings in the Lifelines Cohort Study.

Background: Low-grade systemic inflammation is implicated in the pathogenesis of various neuropsychiatric conditions affecting mood and cognition. While much of the evidence concerns depression, large-scale population studies of anxiety, affect, and cognitive function are scarce. Importantly, causality remains unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognitive performance in the Lifelines Cohort; and whether associations are likely to be causal. Methods: Using data from up to 55,098 (59% female) individuals from the Dutch Lifelines cohort, we tested the cross-sectional and longitudinal associations of C-reactive protein (CRP) with (i) depressive and anxiety disorders; (ii) positive and negative affect scores, and (iii) five cognitive measures assessing attention, psychomotor speed, episodic memory, and executive functioning (figural fluency and working memory). Additionally, we examined the association between inflammatory marker GRSs (CRP, interleukin-6 [IL-6], IL-6 receptor [IL-6R and soluble IL-6R (sIL-6R)], glycoprotein acetyls [GlycA]) on these same outcomes (Nmax=57,946), followed by MR analysis examining evidence of causality of CRP on outcomes (Nmax=23,268). In genetic analyses, all GRSs and outcomes were z-transformed. Results: In non-genetic analyses, higher CRP was associated with diagnosis of any depressive disorder, lower positive and higher negative affect scores, and worse performance on tests of figural fluency, attention, and psychomotor speed after adjusting for potential confounders, although the magnitude of these associations was small. In genetic analyses, CRPGRS was associated with any anxiety disorder (ß=0.002, p=0.037, N=57,047) whereas GlycAGRS was associated with major depressive disorder (ß=0.001, p=0.036; N=57,047). Both CRPGRS (ß=0.006, p=0.035, N=57,946) and GlycAGRS (ß=0.006, p=0.049; N=57,946) were associated with higher negative affect score. Inflammatory marker GRSs were not associated with cognitive performance, except sIL-6RGRS which was associated with poorer memory performance (ß=-0.009, p=0.018, N=36,783). Further examination of the CRP-anxiety association using MR provided some weak evidence of causality (ß=0.12; p=0.054). Conclusions: Genetic and non-genetic analyses provide consistent evidence for an association between CRP and negative affect. Genetic analyses suggest that IL-6 signaling could be relevant for memory, and that the association between CRP and anxiety disorders could be causal. These results suggest that dysregulated immune physiology may impact a broad range of trans-diagnostic affective symptoms. However, given the small effect sizes and multiple tests conducted, future studies are required to investigate whether effects are moderated by sub-groups and whether these findings replicate in other cohorts.

Donor genetic burden for cerebrovascular risk and kidney transplant outcome.

BACKGROUND AND HYPOTHESIS: Kidney grafts from donors who died of stroke and related traits have worse outcomes relative to grafts from both living donors and those who died of other causes. We hypothesise that deceased donors, particularly those who died of stroke, have elevated polygenic burden for cerebrovascular traits. We further hypothesise that this donor polygenic burden is associated with inferior graft outcomes in the recipient. METHODS: Using a dataset of 6666 deceased and living kidney donors from seven different European ancestry transplant cohorts, we investigated the role of polygenic burden for cerebrovascular traits (hypertension, stroke, and intracranial aneurysm (IA)) on donor age of death and recipient graft outcomes. RESULTS: We found that kidney donors who died of stroke had elevated intracranial aneurysm and hypertension polygenic risk scores, compared to healthy controls and living donors. This burden was associated with age of death among donors who died of stroke. Increased donor polygenic risk for hypertension was associated with reduced long term graft survival (HR: 1.44, 95% CI [1.07, 1.93]) and increased burden for hypertension, and intracranial aneurysm was associated with reduced recipient estimated glomerular filtration rate (eGFR) at 1 year. CONCLUSIONS: Collectively, the results presented here demonstrate the impact of inherited factors associated with donors' death on long-term graft function.

Transcriptomics- and Genomics-Guided Drug Repurposing for the Treatment of Vesicular Hand Eczema.

Vesicular hand eczema (VHE), a clinical subtype of hand eczema (HE), showed limited responsiveness to alitretinoin, the only approved systemic treatment for severe chronic HE. This emphasizes the need for alternative treatment approaches. Therefore, our study aimed to identify drug repurposing opportunities for VHE using transcriptomics and genomics data. We constructed a gene network by combining 52 differentially expressed genes (DEGs) from a VHE transcriptomics study with 3 quantitative trait locus (QTL) genes associated with HE. Through network analysis, clustering, and functional enrichment analyses, we investigated the underlying biological mechanisms of this network. Next, we leveraged drug-gene interactions and retrieved pharmaco-transcriptomics data from the DrugBank database to identify drug repurposing opportunities for (V)HE. We developed a drug ranking system, primarily based on efficacy, safety, and practical and pricing factors, to select the most promising drug repurposing candidates. Our results revealed that the (V)HE network comprised 78 genes that yielded several biological pathways underlying the disease. The drug-gene interaction search together with pharmaco-transcriptomics lookups revealed 123 unique drug repurposing opportunities. Based on our drug ranking system, our study identified the most promising drug repurposing opportunities (e.g., vitamin D analogues, retinoids, and immunomodulating drugs) that might be effective in treating (V)HE.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management.

Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.

A genome-wide association study of total child psychiatric problems scores.

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A, PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5, CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

Search for a Functional Genetic Variant Mimicking the Effect of SGLT2 Inhibitor Treatment.

SGLT2 inhibitors (SGLT2i) block renal glucose reabsorption. Due to the unexpected beneficial observations in type 2 diabetic patients potentially related to increased natriuresis, SGLT2i are also studied for heart failure treatment. This study aimed to identify genetic variants mimicking SGLT2i to further our understanding of the potential underlying biological mechanisms. Using the UK Biobank resource, we identified 264 SNPs located in the SLC5A2 gene or within 25kb of the 5' and 3' flanking regions, of which 91 had minor allele frequencies >1%. Twenty-seven SNPs were associated with glycated hemoglobin (HbA1c) after Bonferroni correction in participants without diabetes, while none of the SNPs were associated with sodium excretion. We investigated whether these variants had a directionally consistent effect on sodium excretion, HbA1c levels, and SLC5A2 expression. None of the variants met these criteria. Likewise, we identified no common missense variants, and although four SNPs could be defined as 5' or 3' prime untranslated region variants of which rs45612043 was predicted to be deleterious, these SNPs were not annotated to SLC5A2. In conclusion, no genetic variant was found mimicking SGLT2i based on their location near SLC5A2 and their association with sodium excretion or HbA1c and SLC5A2 expression or function.

A Bidirectional Mendelian Randomization Study to evaluate the causal role of reduced blood vitamin D levels with type 2 diabetes risk in South Asians and Europeans.

CONTEXT: Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent. OBJECTIVES AND METHODS: To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration. RESULTS: Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10-32; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10-78; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument. CONCLUSION: Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.

Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes.

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

GWASinspector: comprehensive quality control of genome-wide association study results.

SUMMARY: Quality control (QC) of genome wide association study (GWAS) result files has become increasingly difficult due to advances in genomic technology. The main challenges include continuous increases in the number of polymorphic genetic variants contained in recent GWASs and reference panels, the rising number of cohorts participating in a GWAS consortium, and inclusion of new variant types. Here, we present GWASinspector, a flexible R package for comprehensive QC of GWAS results. This package is compatible with recent imputation reference panels, handles insertion/deletion and multi-allelic variants, provides extensive QC reports and efficiently processes big data files. Reference panels covering three human genome builds (NCBI36, GRCh37 and GRCh38) are available. GWASinspector has a user friendly design and allows easy set-up of the QC pipeline through a configuration file. In addition to checking and reporting on individual files, it can be used in preparation of a meta-analysis by testing for systemic differences between studies and generating cleaned, harmonized GWAS files. Comparison with existing GWAS QC tools shows that the main advantages of GWASinspector are its ability to more effectively deal with insertion/deletion and multi-allelic variants and its relatively low memory use. AVAILABILITY AND IMPLEMENTATION: Our package is available at The Comprehensive R Archive Network (CRAN): https://CRAN.R-project.org/package=GWASinspector. Reference datasets and a detailed tutorial can be found at the package website at http://gwasinspector.com/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genetic Determinants of Serum Calcification Propensity and Cardiovascular Outcomes in the General Population.

BACKGROUND: Serum calciprotein particle maturation time (T50), a measure of vascular calcification propensity, is associated with cardiovascular morbidity and mortality. We aimed to identify genetic loci associated with serum T50 and study their association with cardiovascular disease and mortality. METHODS: We performed a genome-wide association study of serum T50 in 2,739 individuals of European descent participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, followed by a two-sample Mendelian randomization (MR) study to examine causal effects of T50 on cardiovascular outcomes. Finally, we examined associations between T50 loci and cardiovascular outcomes in 8,566 community-dwelling participants in the Rotterdam study. RESULTS: We identified three independent genome-wide significant single nucleotide polymorphism (SNPs) in the AHSG gene encoding fetuin-A: rs4917 (p = 1.72 × 10-101), rs2077119 (p = 3.34 × 10-18), and rs9870756 (p = 3.10 × 10-8), together explaining 18.3% of variation in serum T50. MR did not demonstrate a causal effect of T50 on cardiovascular outcomes in the general population. Patient-level analyses revealed that the minor allele of rs9870756, which explained 9.1% of variation in T50, was associated with a primary composite endpoint of all-cause mortality or cardiovascular disease [odds ratio (95% CI) 1.14 (1.01-1.28)] and all-cause mortality alone [1.14 (1.00-1.31)]. The other variants were not associated with clinical outcomes. In patients with type 2 diabetes or chronic kidney disease, the association between rs9870756 and the primary composite endpoint was stronger [OR 1.40 (1.06-1.84), relative excess risk due to interaction 0.54 (0.01-1.08)]. CONCLUSIONS: We identified three SNPs in the AHSG gene that explained 18.3% of variability in serum T50 levels. Only one SNP was associated with cardiovascular outcomes, particularly in individuals with type 2 diabetes or chronic kidney disease.