Publications by authors named "Vincenzo Forgetta"

60 Publications

Health Effects of Calcium: Evidence From Mendelian Randomization Studies.

JBMR Plus 2021 Nov 31;5(11):e10542. Epub 2021 Aug 31.

Lady Davis Institute, Jewish General Hospital McGill University Montréal QC Canada.

Calcium is widely used in conjunction with vitamin D to prevent osteoporosis. The use of calcium supplementation is also promoted for its potential benefits in lowering the risk for metabolic syndromes and cancers. However, the causal link between calcium and various health outcomes remains unclear. This review focuses on the evidence from 24 Mendelian randomization (MR) studies that were designed to minimize bias from confounding and reverse causation. These MR studies evaluated the effect of lifelong genetically higher serum calcium levels on various health outcomes. Overall, available MR studies found no conclusive effects of serum calcium levels on bone mineral density and fracture, ischemic stroke and heart failure, cancers, type 2 diabetes, Parkinson disease, or offspring birth weight. However, a higher serum calcium concentration was reported to have estimated causal effects on increased risks for coronary artery disease (especially myocardial infarction), migraine, renal colic, allergy/adverse effect of penicillin, and reduced risks for osteoarthrosis and osteoarthritis. In conclusion, supplementation of calcium in individuals from the general population is not predicted to influence the risk of most investigated diseases to date. Moreover, long-term high serum calcium concentrations may result in adverse health outcomes. © 2021 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbm4.10542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567492PMC
November 2021

Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian Randomization Study.

Diabetes Care 2021 Nov 10. Epub 2021 Nov 10.

Research Center of the Sainte-Justine University Hospital, University of Montreal, Montreal, Quebec, Canada

Objective: To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR).

Research Design And Methods: We used a large-scale two-sample MR study, using genetic determinants (protein quantitative trait loci [pQTL]) of up to 1,611 circulating proteins from five large genome-wide association studies, to screen for causal associations of these proteins with type 1 diabetes risk in 9,684 case subjects with type 1 diabetes and 15,743 control subjects. Further, pleiotropy-robust MR methods were used in sensitivity analyses using both and -pQTL.

Results: We found that a genetically predicted SD increase in signal regulatory protein γ (SIRPG) level was associated with increased risk of type 1 diabetes risk (MR odds ratio [OR] 1.66 [95% 1.36-2.03]; = 7.1 × 10). The risk of type 1 diabetes increased almost twofold per genetically predicted standard deviation (SD) increase in interleukin-27 Epstein-Barr virus-induced 3 (IL27-EBI3) protein levels (MR OR 1.97 [95% CI 1.48-2.62]; = 3.7 × 10). However, an SD increase in chymotrypsinogen B1 (CTRB1) was associated with decreased risk of type 1 diabetes (MR OR 0.84 [95% CI 0.77-0.90]; = 6.1 × 10). Sensitivity analyses using MR methods testing for pleiotropy while including -pQTL showed similar results. While the MR-Egger suggested no pleotropic effect ( value MR-Egger intercept = 0.31), there was evidence of pleiotropy in MR-PRESSO ( value global test = 0.006).

Conclusions: We identified three novel circulating protein biomarkers associated with type 1 diabetes risk using an MR approach. These biomarkers are promising targets for development of drugs and/or of screening tools for early prediction of type 1 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc21-1049DOI Listing
November 2021

Block coordinate descent algorithm improves variable selection and estimation in error-in-variables regression.

Genet Epidemiol 2021 Dec 1;45(8):874-890. Epub 2021 Sep 1.

Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Québec, Canada.

Medical research increasingly includes high-dimensional regression modeling with a need for error-in-variables methods. The Convex Conditioned Lasso (CoCoLasso) utilizes a reformulated Lasso objective function and an error-corrected cross-validation to enable error-in-variables regression, but requires heavy computations. Here, we develop a Block coordinate Descent Convex Conditioned Lasso (BDCoCoLasso) algorithm for modeling high-dimensional data that are only partially corrupted by measurement error. This algorithm separately optimizes the estimation of the uncorrupted and corrupted features in an iterative manner to reduce computational cost, with a specially calibrated formulation of cross-validation error. Through simulations, we show that the BDCoCoLasso algorithm successfully copes with much larger feature sets than CoCoLasso, and as expected, outperforms the naïve Lasso with enhanced estimation accuracy and consistency, as the intensity and complexity of measurement errors increase. Also, a new smoothly clipped absolute deviation penalization option is added that may be appropriate for some data sets. We apply the BDCoCoLasso algorithm to data selected from the UK Biobank. We develop and showcase the utility of covariate-adjusted genetic risk scores for body mass index, bone mineral density, and lifespan. We demonstrate that by leveraging more information than the naïve Lasso in partially corrupted data, the BDCoCoLasso may achieve higher prediction accuracy. These innovations, together with an R package, BDCoCoLasso, make error-in-variables adjustments more accessible for high-dimensional data sets. We posit the BDCoCoLasso algorithm has the potential to be widely applied in various fields, including genomics-facilitated personalized medicine research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22430DOI Listing
December 2021

Utility of Genetically Predicted Lp(a) (Lipoprotein [a]) and ApoB Levels for Cardiovascular Risk Assessment.

Circ Genom Precis Med 2021 10 31;14(5):e003312. Epub 2021 Aug 31.

Department of Epidemiology, Biostatistics and Occupational Health (H.W., J.B.R.), McGill University, Montréal, Québec, Canada.

Background: Current lipid guidelines suggest measurement of Lp(a) (lipoprotein[a]) and ApoB (apolipoprotein B) for atherosclerotic cardiovascular disease risk assessment. Polygenic risk scores (PRSs) for Lp(a) and ApoB may identify individuals unlikely to have elevated Lp(a) or ApoB and thus reduce such suggested testing.

Methods: PRSs were developed using least absolute shrinkage and selection operator regression among 273 222 and 356 958 UK Biobank participants of white British ancestry for Lp(a) and ApoB, respectively, and validated in separate sets of 60 771 UK Biobank and 15 050 European Prospective Investigation into Cancer and Nutrition-Norfolk participants. We then assessed the proportion of participants who, based on these PRSs, were unlikely to benefit from Lp(a) or ApoB measurements, according to current lipid guidelines.

Results: In the UK Biobank and European Prospective Investigation into Cancer and Nutrition-Norfolk cohorts, the area under the receiver operating curve for the PRS-predicted Lp(a) and ApoB to identify individuals with elevated Lp(a) and ApoB was at least 0.91 (95% CI, 0.90-0.92) and 0.74 (95% CI, 0.73-0.75), respectively. The Lp(a) PRS and measured Lp(a) showed comparable association with atherosclerotic cardiovascular disease incidence, whereas the ApoB PRS was in general less predictive of atherosclerotic cardiovascular disease risk than measured ApoB. In the context of the European Society of Cardiology/European Atherosclerosis Society lipid guidelines, at a 95% sensitivity to identify individuals with elevated Lp(a) and ApoB levels, at least 54% of Lp(a) and 24% of ApoB testing could be reduced by prescreening with a PRS while maintaining a low false-negative rate.

Conclusions: A substantial proportion of suggested testing for elevated Lp(a) and a modest proportion of testing for elevated ApoB could potentially be reduced by prescreening individuals with PRSs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.121.003312DOI Listing
October 2021

Genetically increased circulating FUT3 level leads to reduced risk of Idiopathic Pulmonary Fibrosis: a Mendelian Randomisation Study.

Eur Respir J 2021 Jun 25. Epub 2021 Jun 25.

Department of Human Genetics, McGill University, Montréal, Québec, Canada

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF.To identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data. For instruments we used genetic determinants of circulating proteins which reside to the encoded gene (-SNPs), identified by two genome-wide association studies (GWASs) in European individuals (3301 and 3200 subjects). We then applied MR methods to test if the levels of these circulating proteins influenced IPF susceptibility in the largest IPF GWAS (2668 cases and 8591 controls). We validated the MR results using colocalization analyses to ensure that both the circulating proteins and IPF shared a common genetic signal.MR analyses of 834 proteins found that a one sd increase in circulating FUT3 and FUT5 was associated with a reduced risk of IPF (OR: 0.81, 95%CI: 0.74-0.88, p=6.3×10, and OR: 0.76, 95%CI: 0.68-0.86, p=1.1×10). Sensitivity analyses including multiple- SNPs provided similar estimates both for FUT3 (inverse variance weighted [IVW] OR: 0.84, 95%CI: 0.78-0.91, p=9.8×10, MR-Egger OR: 0.69, 95%CI: 0.50-0.97, p=0.03) and FUT5 (IVW OR: 0.84, 95%CI: 0.77-0.92, p=1.4×10, MR-Egger OR: 0.59, 95%CI: 0.38-0.90, p=0.01) FUT3 and FUT5 signals colocalized with IPF signals, with posterior probabilities of a shared genetic signal of 99.9% and 97.7%. Further transcriptomic investigations supported the protective effects of for IPF.An efficient MR scan of 834 circulating proteins provided evidence that genetically increased circulating FUT3 level is associated with reduced risk of IPF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.03979-2020DOI Listing
June 2021

Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study.

PLoS Med 2021 06 1;18(6):e1003605. Epub 2021 Jun 1.

Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.

Background: Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity.

Methods And Findings: Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency.

Conclusions: In this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1003605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168855PMC
June 2021

Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19.

J Clin Invest 2021 07;131(14)

College of Applied Medical Sciences, Taibah University, Madina, Saudi Arabia.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI147834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279578PMC
July 2021

A Polygenic Risk Score to Predict Future Adult Short Stature Among Children.

J Clin Endocrinol Metab 2021 06;106(7):1918-1928

Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Canada.

Context: Adult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared to mid-parental height.

Objective: To develop a polygenic risk score for adult height and evaluate its clinical utility.

Design: A polygenic risk score was constructed based on meta-analysis of genomewide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.

Subjects: Participants included 442 599 genotyped White British individuals in the UK Biobank and 941 genotyped child-parent trios of European ancestry in the ALSPAC cohort.

Interventions: None.

Main Outcome Measures: Standing height was measured using stadiometer; Standing height 2 SDs below the sex-specific population average was considered as short stature.

Results: Combined with sex, a polygenic risk score captured 71.1% of the total variance in adult height in the UK Biobank. In the ALSPAC cohort, the polygenic risk score was able to identify children who developed adulthood short stature with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of mid-parental height. Combining this polygenic risk score with mid-parental height or only one of the child's parent's height could improve the AUROC to at most 0.90. The polygenic risk score could also substitute mid-parental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood.

Conclusions: A polygenic risk score could be considered as an alternative or adjunct to mid-parental height to improve screening for children at risk of developing short stature in adulthood in European ancestry populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgab215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266463PMC
June 2021

Childhood obesity and multiple sclerosis: A Mendelian randomization study.

Mult Scler 2021 Dec 22;27(14):2150-2158. Epub 2021 Mar 22.

Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada/Department of Human Genetics, McGill University, Montreal, QC, Canada/Department of Medicine, McGill University Montreal, QC, Canada/Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada/Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

Background: Higher childhood body mass index (BMI) has been associated with an increased risk of multiple sclerosis (MS).

Objective: To evaluate whether childhood BMI has a causal influence on MS, and whether this putative effect is independent from early adult obesity and pubertal timing.

Methods: We performed Mendelian randomization (MR) using summary genetic data on 14,802 MS cases and 26,703 controls. Large-scale genome-wide association studies provided estimates for BMI in childhood ( = 47,541) and adulthood ( = 322,154). In multivariable MR, we examined the direct effects of each timepoint and further adjusted for age at puberty. Findings were replicated using the UK Biobank ( = 453,169).

Results: Higher genetically predicted childhood BMI was associated with increased odds of MS (odds ratio (OR) = 1.26/SD BMI increase, 95% confidence interval (CI): 1.07-1.50). However, there was little evidence of a direct effect after adjusting for adult BMI (OR = 1.03, 95% CI: 0.70-1.53). Conversely, the effect of adult BMI persisted independent of childhood BMI (OR = 1.43; 95% CI: 1.01-2.03). The addition of age at puberty did not alter the findings. UK Biobank analyses showed consistent results. Sensitivity analyses provided no evidence of pleiotropy.

Conclusion: Genetic evidence supports an association between childhood obesity and MS susceptibility, mediated by persistence of obesity into early adulthood but independent of pubertal timing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/13524585211001781DOI Listing
December 2021

A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity.

Nat Med 2021 04 25;27(4):659-667. Epub 2021 Feb 25.

Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10), hospitalization (OR = 0.61, P = 8 × 10) and susceptibility (OR = 0.78, P = 8 × 10). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-021-01281-1DOI Listing
April 2021

Improved prediction of fracture risk leveraging a genome-wide polygenic risk score.

Genome Med 2021 02 3;13(1):16. Epub 2021 Feb 3.

Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Room H-413, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec, H3T 1E2, Canada.

Background: Accurately quantifying the risk of osteoporotic fracture is important for directing appropriate clinical interventions. While skeletal measures such as heel quantitative speed of sound (SOS) and dual-energy X-ray absorptiometry bone mineral density are able to predict the risk of osteoporotic fracture, the utility of such measurements is subject to the availability of equipment and human resources. Using data from 341,449 individuals of white British ancestry, we previously developed a genome-wide polygenic risk score (PRS), called gSOS, that captured 25.0% of the total variance in SOS. Here, we test whether gSOS can improve fracture risk prediction.

Methods: We examined the predictive power of gSOS in five genome-wide genotyped cohorts, including 90,172 individuals of European ancestry and 25,034 individuals of Asian ancestry. We calculated gSOS for each individual and tested for the association between gSOS and incident major osteoporotic fracture and hip fracture. We tested whether adding gSOS to the risk prediction models had added value over models using other commonly used clinical risk factors.

Results: A standard deviation decrease in gSOS was associated with an increased odds of incident major osteoporotic fracture in populations of European ancestry, with odds ratios ranging from 1.35 to 1.46 in four cohorts. It was also associated with a 1.26-fold (95% confidence interval (CI) 1.13-1.41) increased odds of incident major osteoporotic fracture in the Asian population. We demonstrated that gSOS was more predictive of incident major osteoporotic fracture (area under the receiver operating characteristic curve (AUROC) = 0.734; 95% CI 0.727-0.740) and incident hip fracture (AUROC = 0.798; 95% CI 0.791-0.805) than most traditional clinical risk factors, including prior fracture, use of corticosteroids, rheumatoid arthritis, and smoking. We also showed that adding gSOS to the Fracture Risk Assessment Tool (FRAX) could refine the risk prediction with a positive net reclassification index ranging from 0.024 to 0.072.

Conclusions: We generated and validated a PRS for SOS which was associated with the risk of fracture. This score was more strongly associated with the risk of fracture than many clinical risk factors and provided an improvement in risk prediction. gSOS should be explored as a tool to improve risk stratification to identify individuals at high risk of fracture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-021-00838-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860212PMC
February 2021

Polygenic Risk Score for Low-Density Lipoprotein Cholesterol Is Associated With Risk of Ischemic Heart Disease and Enriches for Individuals With Familial Hypercholesterolemia.

Circ Genom Precis Med 2021 02 13;14(1):e003106. Epub 2021 Jan 13.

Department of Epidemiology, Biostatistics, and Occupational Health (H.W., S.Z., S.R.B., J.B.R.), Lady Davis Institute, Jewish General Hospital, Montréal, QC, Canada.

Background: The clinical implications of a polygenic risk score (PRS) for LDL-C (low-density lipoprotein cholesterol) are not well understood, both within the general population and individuals with familial hypercholesterolemia (FH).

Methods: We developed the LDL-C PRS using Least Absolute Shrinkage and Selection Operator regression in 377 286 White British participants from UK Biobank and tested its association with LDL-C according to FH variant carrier status in another 41 748 whole-exome sequenced individuals. Next, we tested for an enrichment of FH variant carriers among individuals with severe hypercholesterolemia and low LDL-C PRS. Last, we contrasted the effect of the LDL-C PRS, measured LDL-C and FH variant carrier status on risk of ischemic heart disease among 3010 cases and 38 738 controls.

Results: Among the 41 748 whole-exome sequenced White British individuals, 1-SD increase in the LDL-C PRS was associated with elevated LDL-C among both FH variant carriers (0.34 [95% CI, 0.22-0.47] mmol/L) and noncarriers (0.42 [95% CI, 0.42-0.43] mmol/L). Among individuals with severe hypercholesterolemia, FH variant carriers were enriched in those with a low LDL-C PRS (odds ratio, 2.20 [95% CI, 1.66-2.71] per SD). Each SD increase in the LDL-C PRS was associated with risk of ischemic heart disease to the comparable magnitude as measured LDL-C (odds ratio, 1.24 [95% CI, 1.20-1.29] and odds ratio, 1.15 [95% CI, 1.09-1.23], respectively). The LDL-C PRS was not strongly associated with other traditional ischemic heart disease risk factors.

Conclusions: An LDL-C PRS could be used to identify individuals with a higher probability of harboring FH variants. The association between ischemic heart disease and the LDL-C PRS was comparable to measured LDL-C, likely because the PRS reflects lifetime exposure to LDL-C levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003106DOI Listing
February 2021

Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19.

medRxiv 2020 Dec 21. Epub 2020 Dec 21.

Laboratory Department, Security Forces Hospital, General Directorate of Medical Services, Ministry of Interior, Clinical Laboratory Sciences, Taibah University, Madina, Saudi Arabia.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.12.18.20248226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781338PMC
December 2020

The effect of angiotensin-converting enzyme levels on COVID-19 susceptibility and severity: a Mendelian randomization study.

Int J Epidemiol 2021 03;50(1):75-86

Centre for Clinical Epidemiology Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada.

Background: There has been uncertainty about the safety or benefit of angiotensin-converting enzyme (ACE) inhibitors during the COVID-19 pandemic. We used Mendelian randomization using genetic determinants of serum-ACE levels to test whether decreased ACE levels increase susceptibility to SARS-CoV-2 infection or COVID-19 severity, while reducing potential bias from confounding and reverse causation in observational studies.

Methods: Genetic variants strongly associated with ACE levels, which were nearby the ACE gene, were identified from the ORIGIN trial and a separate genome-wide association study (GWAS) of ACE levels from the AGES cohort. The ORIGIN trial included 4147 individuals of European and Latino ancestries. Sensitivity analyses were performed using a study of 3200 Icelanders. Cohorts from the COVID-19 Host Genetics Initiative GWAS of up to 960 186 individuals of European ancestry were used for COVID-19 susceptibility, hospitalization and severe-disease outcome.

Results: Genetic variants were identified that explain between 18% and 37% of variance in ACE levels. Using genetic variants from the ORIGIN trial, a standard-deviation decrease in ACE levels was not associated with an increase in COVID-19 susceptibility [odds ratio (OR): 1.02, 95% confidence interval (CI): 0.90, 1.15], hospitalization (OR: 0.86, 95% CI: 0.68, 1.08) or severe disease (OR: 0.74, 95% CI: 0.51, 1.06). Using genetic variants from the AGES cohort, the result was similar for susceptibility (OR: 0.98, 95% CI: 0.89, 1.09), hospitalization (OR: 0.86, 95% CI: 0.66, 1.11) and severity (OR: 0.75, 95% CI: 0.50, 1.14). Multiple-sensitivity analyses led to similar results.

Conclusion: Genetically decreased serum ACE levels were not associated with susceptibility to, or severity of, COVID-19 disease. These data suggest that individuals taking ACE inhibitors should not discontinue therapy during the COVID-19 pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ije/dyaa229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799043PMC
March 2021

Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis.

Diabetes Care 2021 02 4;44(2):556-562. Epub 2020 Dec 4.

George Institute for Global Health, University of Oxford, Oxford, U.K.

Objective: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding.

Research Design And Methods: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment.

Results: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08-1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17-1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs.

Conclusions: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc20-1137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818328PMC
February 2021

Genetic Determinants of Antibody-Mediated Immune Responses to Infectious Diseases Agents: A Genome-Wide and HLA Association Study.

Open Forum Infect Dis 2020 Nov 24;7(11):ofaa450. Epub 2020 Sep 24.

Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.

Background: Infectious diseases are causally related to a large array of noncommunicable diseases (NCDs). Identifying genetic determinants of infections and antibody-mediated immune responses may shed light on this relationship and provide therapeutic targets for drug and vaccine development.

Methods: We used the UK biobank cohort of up to 10 000 serological measurements of infectious diseases and genome-wide genotyping. We used data on 13 pathogens to define 46 phenotypes: 15 seropositivity case-control phenotypes and 31 quantitative antibody measurement phenotypes. For each of these, we performed genome-wide association studies (GWAS) using the fastGWA linear mixed model package and human leukocyte antigen (HLA) classical allele and amino acid residue associations analyses using Lasso regression for variable selection.

Results: We included a total of 8735 individuals for case-control phenotypes, and an average (range) of 4286 (276-8555) samples per quantitative analysis. Fourteen of the GWAS yielded a genome-wide significant ( < 5 ×10) locus at the major histocompatibility complex (MHC) on chromosome 6. Outside the MHC, we found a total of 60 loci, multiple associated with Epstein-Barr virus (EBV)-related NCDs (eg, RASA3, MED12L, and IRF4). FUT2 was also identified as an important gene for polyomaviridae. HLA analysis highlighted the importance of DRB1*09:01, DQB1*02:01, DQA1*01:02, and DQA1*03:01 in EBV serologies and of DRB1*15:01 in polyomaviridae.

Conclusions: We have identified multiple genetic variants associated with antibody immune response to 13 infections, many of which are biologically plausible therapeutic or vaccine targets. This may help prioritize future research and drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ofid/ofaa450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641500PMC
November 2020

Individuals with common diseases but with a low polygenic risk score could be prioritized for rare variant screening.

Genet Med 2021 03 28;23(3):508-515. Epub 2020 Oct 28.

Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.

Purpose: Identifying rare genetic causes of common diseases can improve diagnostic and treatment strategies, but incurs high costs. We tested whether individuals with common disease and low polygenic risk score (PRS) for that disease generated from less expensive genome-wide genotyping data are more likely to carry rare pathogenic variants.

Methods: We identified patients with one of five common complex diseases among 44,550 individuals who underwent exome sequencing in the UK Biobank. We derived PRS for these five diseases, and identified pathogenic rare variant heterozygotes. We tested whether individuals with disease and low PRS were more likely to carry rare pathogenic variants.

Results: While rare pathogenic variants conferred, at most, 5.18-fold (95% confidence interval [CI]: 2.32-10.13) increased odds of disease, a standard deviation increase in PRS, at most, increased the odds of disease by 5.25-fold (95% CI: 5.06-5.45). Among diseased patients, a standard deviation decrease in the PRS was associated with, at most, 2.82-fold (95% CI: 1.14-7.46) increased odds of identifying rare variant heterozygotes.

Conclusion: Rare pathogenic variants were more prevalent among affected patients with a low PRS. Therefore, prioritizing individuals for sequencing who have disease but low PRS may increase the yield of sequencing studies to identify rare variant heterozygotes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-01007-7DOI Listing
March 2021

The undiagnosed disease burden associated with alpha-1 antitrypsin deficiency genotypes.

Eur Respir J 2020 12 10;56(6). Epub 2020 Dec 10.

Dept of Human Genetics, McGill University, Montréal, QC, Canada

Alpha-1 antitrypsin deficiency (AATD), mainly due to the PI*ZZ genotype in , is one of the most common inherited diseases. Since it is associated with a high disease burden and partially prevented by smoking cessation, identification of PI*ZZ individuals through genotyping could improve health outcomes.We examined the frequency of the PI*ZZ genotype in individuals with and without diagnosed AATD from UK Biobank, and assessed the associations of the genotypes with clinical outcomes and mortality. A phenome-wide association study (PheWAS) was conducted to reveal disease associations with genotypes. A polygenic risk score (PRS) for forced expiratory volume in 1 s (FEV)/forced vital capacity (FVC) ratio was used to evaluate variable penetrance of PI*ZZ.Among 458 164 European-ancestry participants in UK Biobank, 140 had the PI*ZZ genotype and only nine (6.4%, 95% CI 3.4-11.7%) of them were diagnosed with AATD. Those with PI*ZZ had a substantially higher odds of COPD (OR 8.8, 95% CI 5.8-13.3), asthma (OR 2.0, 95% CI 1.4-3.0), bronchiectasis (OR 7.3, 95%CI 3.2-16.8), pneumonia (OR 2.7, 95% CI 1.5-4.9) and cirrhosis (OR 7.8, 95% CI 2.5-24.6) diagnoses and a higher hazard of mortality (2.4, 95% CI 1.2-4.6), compared to PI*MM (wildtype) (n=398 424). These associations were stronger among smokers. PheWAS demonstrated associations with increased odds of empyema, pneumothorax, cachexia, polycythaemia, aneurysm and pancreatitis. Polygenic risk score and PI*ZZ were independently associated with FEV/FVC <0.7 (OR 1.4 per 1-sd change, 95% CI 1.4-1.5 and OR 4.5, 95% CI 3.0-6.9, respectively).The important underdiagnosis of AATD, whose outcomes are partially preventable through smoking cession, could be improved through genotype-guided diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.01441-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726845PMC
December 2020

Development of a polygenic risk score to improve screening for fracture risk: A genetic risk prediction study.

PLoS Med 2020 07 2;17(7):e1003152. Epub 2020 Jul 2.

Centre for Clinical Epidemiology, Department of Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada.

Background: Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-can identify low-risk individuals who can safely be excluded from a fracture risk screening program.

Methods And Findings: A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed "gSOS", and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N = 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)-based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r2 = 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk.

Conclusions: Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1003152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331983PMC
July 2020

A Polygenic Risk Score as a Risk Factor for Medication-Associated Fractures.

J Bone Miner Res 2020 10 20;35(10):1935-1941. Epub 2020 Jul 20.

Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal, Canada.

Some commonly prescribed drugs are associated with increased risk of osteoporotic fractures. However, fracture risk stratification using skeletal measures is not often performed to identify those at risk before these medications are prescribed. We tested whether a genomically predicted skeletal measure, speed of sound (gSOS) from heel ultrasound, which was developed in 341,449 individuals from UK Biobank and tested in a separate subset consisting of 80,027 individuals, is an independent risk factor for fracture in users of fracture-related drugs (FRDs). To do this, we first assessed 80,014 UK Biobank participants (including 12,678 FRD users) for incident major osteoporotic fracture (MOF, n = 1189) and incident hip fracture (n = 209). Effects of gSOS on incident fracture were adjusted for baseline clinical fracture risk factors. We found that each standard deviation decrease in gSOS increased the adjusted odds of MOF by 42% (95% confidence interval [CI] 1.34-1.51, p < 2 × 10 ) and of hip fracture by 31% (95% CI 1.15-1.50, p = 9 × 10 ). gSOS below versus above the mean increased the adjusted odds of MOF by 79% (95% CI 1.58-2.01, p < 2 × 10 ) and of hip fracture by 42% (95% CI 1.08-1.88, p = 1.3 × 10 ). Among FRD users, each standard deviation decrease in gSOS increased the adjusted odds of MOF by 29% (n = 256, 95% CI 1.14-1.46, p = 7 × 10 ) and of hip fracture by 30% (n = 68, 95% CI 1.02-1.65, p = 0.0335). FRD users with gSOS below versus above the mean had a 54% increased adjusted odds of MOF (95% 1.19-1.99, p = 8.95 × 10 ) and a twofold increased adjusted odds of hip fracture (95% 1.19-3.31, p = 8.5 × 10 ). We therefore showed that genomically predicted heel SOS is independently associated with incident fracture among FRD users. © 2020 American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.4104DOI Listing
October 2020

Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci.

Am J Hum Genet 2020 03 13;106(3):327-337. Epub 2020 Feb 13.

Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; Department of Medicine, McGill University Montreal, QC H3G 1Y6, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC H3A 1A2, Canada; Department of Twin Research and Genetic Epidemiology, King's College London, London WC2R 2LS, UK. Electronic address:

We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrichment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared heritability with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 × 10) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architecture of 25OHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058824PMC
March 2020

Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes.

Diabetes 2020 04 31;69(4):784-795. Epub 2020 Jan 31.

Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency [MAF] >5%). We aimed to identify novel rare or low-frequency (MAF <5%) single nucleotide polymorphisms with large effects on risk of type 1 diabetes. We undertook deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 type 1 diabetes case and 15,705 control subjects from 12 European cohorts. Candidate variants were replicated in a separate cohort of 4,329 case and 9,543 control subjects. Our meta-analysis identified 27 independent variants outside the MHC, among which 3 were novel and had MAF <5%. Three of these variants replicated with < 0.05 and < In silico analysis prioritized a rare variant at 2q24.3 (rs60587303 [C], MAF 0.5%) within the first intron of with an effect size comparable with those of common variants in the and loci (combined [from the discovery and replication cohorts] estimate of odds ratio [OR] 1.97, 95% CI 1.58-2.47, = 2.9 × 10). Pharmacological inhibition of activity in primary murine T cells augmented effector responses through enhancement of interleukin 2 signaling. These findings provide insight into the genetic architecture of type 1 diabetes and have identified rare variants having a large effect on disease risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db19-0831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085253PMC
April 2020

Polygenic risk for coronary heart disease acts through atherosclerosis in type 2 diabetes.

Cardiovasc Diabetol 2020 01 30;19(1):12. Epub 2020 Jan 30.

Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.

Background: Type 2 diabetes increases the risk of coronary heart disease (CHD), yet the mechanisms involved remain poorly described. Polygenic risk scores (PRS) provide an opportunity to understand risk factors since they reflect etiologic pathways from the entire genome. We therefore tested whether a PRS for CHD influenced risk of CHD in individuals with type 2 diabetes and which risk factors were associated with this PRS.

Methods: We tested the association of a CHD PRS with CHD and its traditional clinical risk factors amongst individuals with type 2 diabetes in UK Biobank (N = 21,102). We next tested the association of the CHD PRS with atherosclerotic burden in a cohort of 352 genome-wide genotyped participants with type 2 diabetes who had undergone coronary angiograms.

Results: In the UK Biobank we found that the CHD PRS was strongly associated with CHD amongst individuals with type 2 diabetes (OR per standard deviation increase = 1.50; p = 1.5 × 10). But this CHD PRS was, at best, only weakly associated with traditional clinical risk factors, such as hypertension, hyperlipidemia, glycemic control, obesity and smoking. Conversely, in the angiographic cohort, the CHD PRS was strongly associated with multivessel stenosis (OR = 1.65; p = 4.9 × 10) and increased number of major stenotic lesions (OR = 1.35; p = 9.4 × 10).

Conclusions: Polygenic predisposition to CHD is strongly associated with atherosclerotic burden in individuals with type 2 diabetes and this effect is largely independent of traditional clinical risk factors. This suggests that genetic risk for CHD acts through atherosclerosis with little effect on most traditional risk factors, providing the opportunity to explore new biological pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12933-020-0988-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993460PMC
January 2020

Increased Burden of Common Risk Alleles in Children With a Significant Fracture History.

J Bone Miner Res 2020 05 28;35(5):875-882. Epub 2020 Jan 28.

Lady Davis Institute for Medical Research, Centre for Clinical Epidemiology, Jewish General Hospital, McGill University, Montreal, Canada.

Extreme presentations of common disease in children are often presumed to be of Mendelian etiology, but their polygenic basis has not been fully explored. We tested whether children with significant fracture history and no osteogenesis imperfecta (OI) are at increased polygenic risk for fracture. A childhood significant fracture history was defined as the presence of low-trauma vertebral fractures or multiple long bone fractures. We generated a polygenic score of heel ultrasound-derived speed of sound, termed "gSOS," which predicts risk of osteoporotic fracture. We tested if individuals from three cohorts with significant childhood fracture history had lower gSOS. A Canadian cohort included 94 children with suspected Mendelian osteoporosis, of which 68 had negative OI gene panel. Two Finnish cohorts included 59 children with significant fracture history and 22 with suspected Mendelian osteoporosis, among which 18 had no OI. After excluding individuals with OI and ancestral outliers, we generated gSOS estimates and compared their mean to that of a UK Biobank subset, representing the general population. The average gSOS across all three cohorts (n = 131) was -0.47 SD lower than that in UK Biobank (n = 80,027, p = 1.1 × 10 ). The gSOS of 78 individuals with suspected Mendelian osteoporosis was even lower (-0.76 SD, p = 5.3 × 10 ). Among the 131 individuals with a significant fracture history, we observed 8 individuals with gSOS below minus 2 SD from the mean; their mean lumbar spine DXA-derived bone mineral density Z-score was -1.7 (SD 0.8). In summary, children with significant fracture history but no OI have an increased burden of common risk alleles. This suggests that a polygenic contribution to disease should be considered in children with extreme presentations of fracture. © 2020 American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.3956DOI Listing
May 2020

Genetically Decreased Circulating Vascular Endothelial Growth Factor and Osteoporosis Outcomes: A Mendelian Randomization Study.

J Bone Miner Res 2020 04 6;35(4):649-656. Epub 2020 Jan 6.

Department of Human Genetics, McGill University, Montreal, Canada.

Vascular endothelial growth factor (VEGF) is important for bone formation and has been associated with osteoporosis in humans. Therefore, we conducted a two-sample Mendelian randomization study to test whether genetically decreased circulating VEGF was associated with decreased bone mineral density (BMD) and increased risk of fracture. Summary statistics from a genomewide association study (GWAS) meta-analysis of circulating VEGF level (n = 16,112) were used to identify 10 genetic variants explaining up to 52% of the variance in circulating VEGF levels. GWAS meta-analyses on dual-energy X-ray absorptiometry (DXA)-derived BMD of forearm, lumbar spine, and femoral neck (n = up to 32,735) and BMD estimated from heel calcaneus ultrasound (eBMD) (n = 426,824) were used to assess the effect of genetically lowered circulating VEGF levels on BMD. A GWAS meta-analysis including a total of 76,549 cases and 470,164 controls was used to assess the effect of genetically lowered circulating VEGF levels on risk of fracture. A natural log-transformed pg/mL decrease in circulating VEGF levels was not associated with a decrease in forearm BMD (0.02 standard deviation [SD], 95% confidence interval [CI] -0.024 to 0.064, p = 0.38), lumbar spine BMD (-0.005 SD, 95% CI -0.03 to 0.019, p = 0.67), femoral neck BMD (0.004 SD, 95% CI -0.017 to 0.026, p = 0.68), eBMD (-0.006 SD, 95% CI -0.012 to -0.001, p = 0.031) or risk of fracture (odds ratio = 0.99, 95% CI 0.98 to 1.0, p = 0.37) in inverse-variance-weighted Mendelian randomization analyses. Sensitivity analyses did not provide evidence that our results were influenced by pleiotropy. Genetically lowered circulating VEGF was not associated with a decrease in BMD or increased risk of fracture, suggesting that efforts to influence circulating VEGF level are unlikely to have beneficial effects on osteoporosis outcomes and that previous observational associations of circulating VEGF with BMD were influenced by confounding or reverse causation. © 2019 American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.3937DOI Listing
April 2020

Genetic predisposition to increased serum calcium, bone mineral density, and fracture risk in individuals with normal calcium levels: mendelian randomisation study.

BMJ 2019 08 1;366:l4410. Epub 2019 Aug 1.

Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada

Objective: To determine if genetically increased serum calcium levels are associated with improved bone mineral density and a reduction in osteoporotic fractures.

Design: Mendelian randomisation study.

Setting: Cohorts used included: the UK Biobank cohort, providing genotypic and estimated bone mineral density data; 25 cohorts from UK, USA, Europe, and China, providing genotypic and fracture data; and 17 cohorts from Europe, providing genotypic and serum calcium data (summary level statistics).

Participants: A genome-wide association meta-analysis of serum calcium levels in up to 61 079 individuals was used to identify genetic determinants of serum calcium levels. The UK Biobank study was used to assess the association of genetic predisposition to increased serum calcium with estimated bone mineral density derived from heel ultrasound in 426 824 individuals who had, on average, calcium levels in the normal range. A fracture genome-wide association meta-analysis comprising 24 cohorts and the UK Biobank including a total of 76 549 cases and 470 164 controls, who, on average, also had calcium levels in the normal range was then performed.

Results: A standard deviation increase in genetically derived serum calcium (0.13 mmol/L or 0.51 mg/dL) was not associated with increased estimated bone mineral density (0.003 g/cm, 95% confidence interval -0.059 to 0.066; P=0.92) or a reduced risk of fractures (odds ratio 1.01, 95% confidence interval 0.89 to 1.15; P=0.85) in inverse-variance weighted mendelian randomisation analyses. Sensitivity analyses did not provide evidence of pleiotropic effects.

Conclusions: Genetic predisposition to increased serum calcium levels in individuals with normal calcium levels is not associated with an increase in estimated bone mineral density and does not provide clinically relevant protection against fracture. Whether such predisposition mimics the effect of short term calcium supplementation is not known. Given that the same genetically derived increase in serum calcium is associated with an increased risk of coronary artery disease, widespread calcium supplementation in the general population could provide more risk than benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmj.l4410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669416PMC
August 2019

Laboratory-developed test for detection of acute Clostridium difficile infections with the capacity for quantitative sample normalization.

Diagn Microbiol Infect Dis 2019 Oct 10;95(2):113-118. Epub 2019 May 10.

Department of Medical Microbiology, Jewish General Hospital, Quebec, Canada; McGill University, Faculty of Medicine, Montreal, Quebec, Canada. Electronic address:

We describe a laboratory-developed test intended for the detection of acute Clostridium difficile infections (CDI) with the capacity for quantitative sample normalization. The test is based on the detection of the tcdB gene. However, this biomarker is also present among people without symptoms, implying that individuals with diarrhea, not caused by C. difficile may nonetheless test positive. Therefore, clinical diagnosis based on this format of testing can be challenging. In order to improve diagnostic assays capability, tcdB-based quantification methods were suggested as a potential solution, however they did not increase clinical specificity. We report methodology for a dual biomarker monitoring (total bacterial load and tcdB assay), allowing for the calculation of the relative presence of tcdB in the total bacterial population in the tested samples. We believe that this approach is clinically relevant to current assays and can improve CDI testing algorithms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.diagmicrobio.2019.04.017DOI Listing
October 2019

Author Correction: An atlas of genetic influences on osteoporosis in humans and mice.

Nat Genet 2019 05;51(5):920

University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.

In the version of this article initially published, in Fig. 5a, the data in the right column of 'DAAM2 gRNA1' were incorrectly plotted as circles indicating 'untreated' rather than as squares indicating 'treated'. The error has been corrected in the HTML and PDF versions of the article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0415-xDOI Listing
May 2019

Effect of age at puberty on risk of multiple sclerosis: A mendelian randomization study.

Neurology 2019 04 20;92(16):e1803-e1810. Epub 2019 Mar 20.

From the Department of Neurology and Neurosurgery (A.H.), Department of Human Genetics (J.A.M., V.F., J.B.R.), Department of Medicine (J.B.R.), and Department of Epidemiology, Biostatistics and Occupational Health (J.B.R.), McGill University; Centre for Clinical Epidemiology (A.H., J.A.M., V.F., J.B.R.), Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada; MRC Integrative Epidemiology Unit (R.M., G.D.S.), School of Social and Community Medicine, and Population Health Sciences (R.M., G.D.S., S.J.S.), Bristol Medical School, University of Bristol; Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge; and Department of Twin Research and Genetic Epidemiology (J.B.R.), King's College London, UK.

Objective: To investigate the potential for a causal effect of age at puberty on multiple sclerosis (MS) susceptibility using a mendelian randomization (MR) approach.

Methods: We used 372 genetic variants strongly associated with age at menarche in a genome-wide association study (GWAS) involving 329,245 women. The genetic architecture of pubertal timing across both sexes is highly correlated (genetic correlation [ ] = 0.75, = 1.2 × 10), allowing these variants to provide reliable insight into pubertal timing in males as well. The effect of pubertal timing on risk of MS was measured with summary statistics from a GWAS of 14,802 cases with MS and 26,703 controls from the International Multiple Sclerosis Genetics Consortium. Multivariable MR controlling for effects of body mass index (BMI) using genetic data from additional consortia investigated whether pubertal effects on MS were dependent on weight status.

Results: A 1-year increase in genetically predicted age at puberty decreased odds of MS by 8% (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.86-0.99, = 0.03). However, multivariable MR analysis showed that after accounting for effects on adult BMI, the association of age at puberty with MS susceptibility attenuated (OR 0.96, 95% CI 0.88-1.04, = 0.36). Similar results were obtained when childhood BMI was incorporated. Sensitivity analyses provided no evidence of major bias from genetic pleiotropy.

Conclusions: We found support for an association between higher age at puberty and decreased risk of MS with a magnitude comparable to that reported in observational studies. This effect appears to be largely mediated by the strong association between age at puberty and obesity. A large causal effect of pubertal timing independent of BMI is unlikely.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550505PMC
April 2019

An atlas of genetic influences on osteoporosis in humans and mice.

Nat Genet 2019 02 31;51(2):258-266. Epub 2018 Dec 31.

University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0302-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358485PMC
February 2019
-->