Biology subjects

Bovijn, J.

Publications and source records attributed to Bovijn, J..

6 recordsLinked to original sources

bioRxiv2025

Metabolomics Ex/GWAS in the Amish reveals novel insights into cardiometabolic disease pathways

We conducted an exome and genome-wide association study (Ex/GWAS) of 1,015 metabolites in serum samples from 5,981 Amish adults. We identified 149 functional or likely functional genetic variants, based on CADD scores significantly associated (P < 5.8 x 10-8) with 519 metabolite levels, 69 of which were >10-fold enriched in the Amish versus Europeans in gnomAD. We discovered novel associations involving a PCK2 splice-donor variant (rs138881435) and metabolites important for energy metabolism and mitochondrial function. In UK Biobank participants, this variant was associated with increased longitudinal relaxation time (T1) values on liver MRI suggesting increased inflammation and fibrosis. Furthermore, we found novel associations involving ENPEP stop-gain variant (rs33966350) and peptide and amino acid metabolite levels, implicating ENPEPs roles in blood pressure regulation. Additional known and novel genetic variant-metabolite associations were identified including genes involved in Amish-enriched Mendelian diseases and cardiometabolic traits, providing insights into underlying mechanisms of these disorders.

genomics↗

bioRxiv2020

Genome-wide study identifies association between HLA-B*55:01 and penicillin allergy

BackgroundHypersensitivity reactions to drugs are often unpredictable and can be life-threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. MethodsWe extracted data from the electronic health records of 52,000 Estonian and 500,000 UK biobank participants to study the role of genetic variation in the occurrence of penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from up to 22,554 and 488,377 individuals from the Estonian and UK cohorts, respectively, to further fine-map the human leukocyte antigen (HLA) association and replicated our results in two additional cohorts involving a total of 1.14 million individuals. ResultsGenome-wide meta-analysis of penicillin allergy revealed a significant association located in the HLA region on chromosome 6. The signal was further fine-mapped to the HLA-B*55:01 allele (OR 1.47 95% CI 1.37-1.58, P-value 4.63x10-26) and confirmed by independent replication in two cohorts. The meta-analysis of all four cohorts in the study revealed a strong association of HLA-B*55:01 allele with penicillin allergy (OR 1.33 95% CI 1.29-1.37, P-value 2.23x10-72). In silico follow-up suggests a potential effect on T lymphocytes at HLA-B*55:01. ConclusionWe present the first robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.

genetics↗

bioRxiv2020

Colocalization highlights genes in hypothalamic-pituitary-gonadal axis as potentially mediating polycystic ovary syndrome risk

Polycystic ovary syndrome (PCOS) is a common disease in women with consequences for reproductive, metabolic and psychological health. Women with PCOS have disrupted signalling in the hypothalamic-pituitary-gonadal axis and studies have indicated that the disease has a large genetic component. While a recent genome-wide association study of PCOS performed in up to 10,074 cases and 103,164 controls of European decent identified 14 PCOS-associated regions, much of the disease pathophysiology remains unclear. Here, we use a Bayesian colocalization approach to highlight genes that may have a potential role in PCOS pathophysiology and thus are of particular interest for further functional follow-up. We evaluated the posterior probabilities of shared causal variants between PCOS genetic risk loci and intermediate cellular phenotypes in one protein and two expression quantitative trait locus datasets, respectively. Sample sizes ranged from 80 to 31,684. In total, we identified seven proteins or genes with evidence of a shared causal variant for almost a third of PCOS signals, including follicle stimulating hormone (FSH) and the genes ERBB3, IKZF4, RPS26, SUOX, ZFP36L2, and C8orf49. Several of these genes and proteins have been implicated in the hypothalamic-pituitary-gonadal signalling pathway. In summary, our results suggest potential effector proteins and genes for PCOS association signals. This highlights genes for functional follow-up in order to demonstrate a causal role in PCOS pathophysiology.

genetics↗

bioRxiv2019

Lifelong genetically lowered sclerostin and risk of cardiovascular disease.

BackgroundInhibition of sclerostin is a novel therapeutic approach to lowering fracture risk. However, phase III randomised controlled trials (RCTs) of romosozumab, a monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events. MethodsWe used two independent genetic variants (rs7209826 and rs188810925) in SOST (encoding sclerostin) associated with bone mineral density (BMD) as proxies for therapeutic inhibition of sclerostin. We estimated the effects on risk of osteoporosis, fracture, coronary heart disease (CHD) and a further 22 cardiometabolic risk factors and diseases, by combining data from up to 478,967 participants of European ancestry from three prospective cohorts and up to 1,030,836 participants from nine GWAS consortia. In addition, we performed meta-analyses of cardiovascular outcome data from phase III RCTs of romosozumab. ResultsMeta-analysis of RCTs identified a higher risk of cardiac ischemic events in patients randomised to romosozumab (25 events among 4,298 individuals; odds ratio [OR] 2{middle dot}98; 95% confidence interval [CI], 1{middle dot}18 to 7{middle dot}55; P=0{middle dot}017). Scaled to the equivalent dose of romosozumab (210mg/month; 0{middle dot}09 g/cm2 higher BMD), the SOST variants associated with lower risk of fracture (OR, 0{middle dot}59; 95% CI, 0{middle dot}54-0{middle dot}66; P= 1{middle dot}4x10-24), and osteoporosis (OR, 0{middle dot}43; 95% CI, 0{middle dot}36-0{middle dot}52; P=2{middle dot}4x10-18). The SOST variants associated with higher risk of myocardial infarction and/or coronary revascularisation (69,649 cases; OR, 1{middle dot}18; 95% CI, 1{middle dot}06-1{middle dot}32; P=0{middle dot}003) and type 2 diabetes (OR 1{middle dot}15; 95% CI, 1{middle dot}05-1{middle dot}27; P=0{middle dot}003), higher systolic blood pressure (1{middle dot}3mmHg; 95% CI 0{middle dot}8-1{middle dot}9; P=5{middle dot}9x10-6) and waist-to-hip-ratio adjusted for BMI (0{middle dot}05 SDs; 95% CI, 0{middle dot}02 to 0{middle dot}08; P=8{middle dot}5x10-4). ConclusionsGenetically and therapeutically lowered sclerostin leads to higher risk of cardiovascular events. Rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors is warranted.

genetics↗

bioRxiv2019

Causal relevance of obesity on the leading causes of death in women and men: A Mendelian randomization study

BackgroundObesity traits are causally implicated with risk of cardiometabolic diseases. It remains unclear whether there are similar causal effects of obesity traits on other non-communicable diseases. Also, it is largely unexplored whether there are any sex-specific differences in the causal effects of obesity traits on cardiometabolic diseases and other leading causes of death. We therefore tested associations of sex-specific genetic risk scores (GRSs) for body mass index (BMI), waist-hip-ratio (WHR), and WHR adjusted for BMI (WHRadjBMI) with leading causes of mortality, using a Mendelian randomization (MR) framework. Methods and FindingsWe constructed sex-specific GRSs for BMI, WHR, and WHRadjBMI, including 565, 324, and 338 genetic variants, respectively. These GRSs were then used as instrumental variables to assess associations between the obesity traits and leading causes of mortality using an MR design in up to 422,414 participants from the UK Biobank. We also investigated associations with potential mediators and risk factors, including smoking, glycemic and blood pressure traits. Sex-differences were subsequently assessed by Cochrans Q-test (Phet). Up to 227,717 women and 194,697 men with mean (standard deviation) age 56.6 (7.9) and 57.0 (8.1) years, body mass index 27.0 (5.1) and 27.9 (4.2) kg/m2 and waist-hip-ratio 0.82 (0.07) and 0.94 (0.07), respectively, were included. Mendelian randomization analysis showed that obesity causes coronary artery disease, stroke (particularly ischemic), chronic obstructive pulmonary disease, lung cancer, type 2 and 1 diabetes mellitus, non-alcoholic fatty liver disease, chronic liver disease, and acute and chronic renal failure. A 1 standard deviation higher body mass index led to higher risk of type 2 diabetes in women (OR 3.81; 95% CI 3.42-4.25, P=8.9x10-130) than in men (OR 2.78; 95% CI 2.57-3.02, P=1.0x10-133, Phet=5.1x10-6). Waist-hip-ratio led to a higher risk of chronic obstructive pulmonary disease (Phet=5.5x10-6) and higher risk of chronic renal failure (Phet=1.3x10-4) in men than women. A limitation of MR studies is potential bias if the genetic variants are directly associated with confounders (pleiotropy), but sensitivity analyses such as MR-Egger supported the main findings. Our study was also limited to people of European descent and results may differ in people of other ancestries. ConclusionsObesity traits have an etiological role in the majority of the leading global causes of death. Sex differences exist in the effects of obesity traits on risk of type 2 diabetes, chronic obstructive pulmonary disease, and renal failure, which may have implications on public health.

epidemiology↗

bioRxiv2018

GWAS identifies novel risk locus for erectile dysfunction and implicates hypothalamic neurobiology and diabetes in etiology

GWAS of erectile dysfunction (ED) in 6,175 cases among 223,805 European men identified one new locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71x10-14), located between MCHR2 and SIM1. In-silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation; Mendelian randomization indicates genetic risk of type 2 diabetes causes ED. Our findings provide novel insights into the biological underpinnings of ED.

genomics↗