Publications by authors named "Daniel I Chasman"

323 Publications

Sugar-sweetened Beverage Consumption May Modify Associations between Genetic Variants in the CHREBP Locus and HDL-C and TG Concentrations.

Circ Genom Precis Med 2021 Jul 16. Epub 2021 Jul 16.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

- Carbohydrate responsive element binding protein (ChREBP) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) concentrations. We hypothesized SSB consumption would modify the association between genetic variants in the locus and dyslipidemia. - Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (N=63,599) and the UK Biobank (UKB) (N=59,220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and TG concentrations using linear regression models. A total of 1,606 single-nucleotide polymorphisms (SNPs) within or near were considered. SSB consumption was estimated from validated questionnaires and participants were grouped by their estimated intake. - In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers [β (95% CI) = 2.12 (1.16, 3.07) mg/dl; <0.0002], but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for two additional variants (rs35709627 and rs71556736). For TG, rs55673514 was positively associated with TG concentrations only among the highest SSB consumers [β (95% CI): 0.06 (0.02, 0.09) per allele count for log(mg/dl), =0.001], but not the lowest SSB consumers (=0.84; =0.0005). - Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in TG concentrations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003288DOI Listing
July 2021

Effects of thyroid function on hemostasis, coagulation, and fibrinolysis: a Mendelian Randomization study.

Thyroid 2021 Jul 1. Epub 2021 Jul 1.

Aarhus University Hospital, 11297, Steno Diabetes Center Aarhus, Hedeager 3, Aarhus, Aarhus, Denmark, 8000;

Background: Untreated hypothyroidism is associated with acquired von Willebrand syndrome, and hyperthyroidism is associated with increased thrombosis risk. However, the causal effects of thyroid function on hemostasis, coagulation, and fibrinolysis are unknown.

Methods: In a two sample Mendelian Randomization (MR) study with genome-wide association variants, we assessed causality of genetically predicted hypothyroidism (N=134,641), normal-range TSH (N=54,288) and fT4 (N=49,269), hyperthyroidism (N=51,823), and thyroid peroxidase antibody positivity (TPOAb) (N=25,821) on coagulation (APTT, VWF, factor VIII, PT, factor VII, fibrinogen) and fibrinolysis (D-dimer, TPA, PAI1) from the CHARGE Hemostasis Consortium (N=2,583-120,246). Inverse-variance-weighted random effects was the main MR analysis followed by sensitivity analyses. Two-sided p<0.05 was nominally significant and p<0.0011[=0.05/(5 exposures x 9 outcomes)] was Bonferroni significant for the main MR analysis.

Results: Genetically increased TSH was associated with decreased VWF [beta(SE)=-0.020(0.006), p=0.001] and with decreased fibrinogen [beta(SE)=-0.008(0.002), p=0.001]. Genetically increased fT4 was associated with increased VWF [beta(SE)=0.028(0.011), p=0.012]. Genetically predicted hyperthyroidism was associated with increased VWF [beta(SE)=0.012(0.004), p=0.006] and increased FVIII [beta(SE)=0.013(0.005), p=0.007]. Genetically predicted hypothyroidism and hyperthyroidism were associated with decreased TPA [beta(SE)=-0.009(0.024), p=0.024] and increased TPA [beta(SE)=0.022(0.008), p=0.008], respectively. MR sensitivity analyses showed similar direction but lower precision. Other coagulation and fibrinolytic factors were inconclusive.

Conclusions: In the largest genetic studies currently available, genetically increased TSH and fT4 may be associated with decreased and increased synthesis of VWF, respectively. Since Bonferroni correction may be too conservative given the correlation between the analyzed traits, we cannot reject nominal associations of thyroid traits with coagulation or fibrinolytic factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2021.0055DOI Listing
July 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Genome-wide gene-diet interaction analysis in the UK Biobank identifies novel effects on Hemoglobin A1c.

Hum Mol Genet 2021 Apr 16. Epub 2021 Apr 16.

Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.

Diet is a significant modifiable risk factor for type 2 diabetes (T2D), and its effect on disease risk is under partial genetic control. Identification of specific gene-diet interactions (GDIs) influencing risk biomarkers such as glycated hemoglobin (HbA1c) is a critical step towards precision nutrition for T2D prevention, but progress has been slow due to limitations in sample size and accuracy of dietary exposure measurement. We leveraged the large UK Biobank (UKB) cohort and a diverse group of dietary exposures, including 30 individual dietary traits and 8 empirical dietary patterns, to conduct genome-wide interaction studies in ~ 340 000 European-ancestry participants to identify novel GDIs influencing HbA1c. We identified five variant-dietary trait pairs reaching genome-wide significance (p < 5 × 10-8): two involved dietary patterns (meat pattern with rs147678157 and a fruit & vegetable-based pattern with rs3010439) and three involved individual dietary traits (bread consumption with rs62218803, dried fruit consumption with rs140270534, and milk type [dairy vs. other] with 4:131148078_TAGAA_T). These were affected minimally by adjustment for geographical and lifestyle-related confounders, and four of the five variants lacked genetic main effects that would have allowed their detection in a traditional genome-wide association study for HbA1c. Notably, multiple loci near transient receptor potential subfamily M genes (TRPM2 and TRPM3) interacted with carbohydrate-containing food groups. These interactions were further characterized using non-European UKB subsets and alternative measures of glycemia (fasting glucose and follow-up HbA1c measurements). Our results highlight GDIs influencing HbA1c for future investigation, while reinforcing known challenges in detecting and replicating GDIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab109DOI Listing
April 2021

Association Between Hemostatic Profile and Migraine: A Mendelian Randomization Analysis.

Neurology 2021 05 1;96(20):e2481-e2487. Epub 2021 Apr 1.

From the Division of Preventive Medicine (Y.G., P.M. Rist, P.M. Ridker, D.C.), Brigham and Women's Hospital; Harvard Medical School (Y.G., P.M. Rist, P.M. Ridker, D.I.C.); Department of Epidemiology (Y.G., P.M. Rist, P.M. Ridker, T.K., D.C.), Harvard T.H. Chan School of Public Health, Boston, MA; Genomics of Complex Diseases (M.S.-L.), Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain; Cardiovascular Medicine Unit, Department of Medicine (M.S.-L.), Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences (P.d.V.), School of Public Health, The University of Texas Health Science Center at Houston; Department of Epidemiology (N.S.), University of Washington; Kaiser Permanente Washington Health Research Institute (N.S.), Seattle; Seattle Epidemiologic Research and Information Center (N.S.), Department of Veterans Affairs Office of Research and Development, WA; and Institute of Public Health (T.K.), Charité-Universitätsmedizin Berlin, Germany.

Objective: To assess support for a causal relationship between hemostatic measures and migraine susceptibility using genetic instrumental analysis.

Methods: Two-sample Mendelian randomization instrumental analyses leveraging available genome-wide association study (GWAS) summary statistics were applied to hemostatic measures as potentially causal for migraine and its subtypes, migraine with aura (MA) and migraine without aura (MO). Twelve blood-based measures of hemostasis were examined, including plasma level or activity of 8 hemostatic factors and 2 fibrinopeptides together with 2 hemostasis clinical tests.

Results: There were significant instrumental effects between increased coagulation factor VIII activity (FVIII; odds ratio [95% confidence interval] 1.05 [1.03, 1.08]/SD, = 6.08 × 10), von Willebrand factor level (vWF; 1.05 [1.03, 1.08]/SD, = 2.25 × 10), and phosphorylated fibrinopeptide A level (1.13 [1.07, 1.19]/SD, = 5.44 × 10) with migraine susceptibility. When extended to migraine subtypes, FVIII, vWF, and phosphorylated fibrinopeptide A showed slightly stronger effects with MA than overall migraine. Fibrinogen level was inversely linked with MA (0.76 [0.64, 0.91]/SD, = 2.32 × 10) but not overall migraine. None of the hemostatic factors was linked with MO. In sensitivity analysis, effects for fibrinogen and phosphorylated fibrinopeptide A were robust, whereas independent effects of FVIII and vWF could not be distinguished, and FVIII associations were potentially affected by pleiotropy at the locus. Causal effects from migraine to the hemostatic measures were not supported in reverse Mendelian randomization. However, MA was not included due to lack of instruments.

Conclusions: The findings support potential causality of increased FVIII, vWF, and phosphorylated fibrinopeptide A and decreased fibrinogen in migraine susceptibility, especially for MA, potentially revealing etiologic relationships between hemostasis and migraine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205479PMC
May 2021

Prospective evaluation of a breast-cancer risk model integrating classical risk factors and polygenic risk in 15 cohorts from six countries.

Int J Epidemiol 2021 Mar 23. Epub 2021 Mar 23.

Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.

Background: Rigorous evaluation of the calibration and discrimination of breast-cancer risk-prediction models in prospective cohorts is critical for applications under clinical guidelines. We comprehensively evaluated an integrated model incorporating classical risk factors and a 313-variant polygenic risk score (PRS) to predict breast-cancer risk.

Methods: Fifteen prospective cohorts from six countries with 239 340 women (7646 incident breast-cancer cases) of European ancestry aged 19-75 years were included. Calibration of 5-year risk was assessed by comparing expected and observed proportions of cases overall and within risk categories. Risk stratification for women of European ancestry aged 50-70 years in those countries was evaluated by the proportion of women and future cases crossing clinically relevant risk thresholds.

Results: Among women <50 years old, the median (range) expected-to-observed ratio for the integrated model across 15 cohorts was 0.9 (0.7-1.0) overall and 0.9 (0.7-1.4) at the highest-risk decile; among women ≥50 years old, these were 1.0 (0.7-1.3) and 1.2 (0.7-1.6), respectively. The proportion of women identified above a 3% 5-year risk threshold (used for recommending risk-reducing medications in the USA) ranged from 7.0% in Germany (∼841 000 of 12 million) to 17.7% in the USA (∼5.3 of 30 million). At this threshold, 14.7% of US women were reclassified by adding the PRS to classical risk factors, with identification of 12.2% of additional future cases.

Conclusion: Integrating a 313-variant PRS with classical risk factors can improve the identification of European-ancestry women at elevated risk who could benefit from targeted risk-reducing strategies under current clinical guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ije/dyab036DOI Listing
March 2021

Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries.

Genetics 2021 May;218(1)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/genetics/iyab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128395PMC
May 2021

Variation in VKORC1 Is Associated with Vascular Dementia.

J Alzheimers Dis 2021 ;80(3):1329-1337

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Background: The genetic variant rs9923231 (VKORC1) is associated with differences in the coagulation of blood and consequentially with sensitivity to the drug warfarin. Variation in VKORC1 has been linked in a gene-based test to dementia/Alzheimer's disease in the parents of participants, with suggestive evidence for an association for rs9923231 (p = 1.8×10-7), which was included in the genome-wide significant KAT8 locus.

Objective: Our study aimed to investigate whether the relationship between rs9923231 and dementia persists only for certain dementia sub-types, and if those taking warfarin are at greater risk.

Methods: We used logistic regression and data from 238,195 participants from UK Biobank to examine the relationship between VKORC1, risk of dementia, and the interplay with warfarin use.

Results: Parental history of dementia, APOE variant, atrial fibrillation, diabetes, hypertension, and hypercholesterolemia all had strong associations with vascular dementia (p < 4.6×10-6). The T-allele in rs9923231 was linked to a lower warfarin dose (βperT - allele = -0.29, p < 2×10-16) and risk of vascular dementia (OR = 1.17, p = 0.010), but not other dementia sub-types. However, the risk of vascular dementia was not affected by warfarin use in carriers of the T-allele.

Conclusion: Our study reports for the first time an association between rs9923231 and vascular dementia, but further research is warranted to explore potential mechanisms and specify the relationship between rs9923231 and features of vascular dementia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-201256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150662PMC
January 2021

Association of Genetic Variants With Migraine Subclassified by Clinical Symptoms in Adult Females.

Front Neurol 2020 12;11:617472. Epub 2021 Feb 12.

Harvard Medical School, Boston, MA, United States.

Migraine is heritable and formally diagnosed by structured criteria that require presence of some but not all possible migraine symptoms which include aura, several distinct manifestations of pain, nausea/vomiting, and sensitivity to light or sound. The most recent genome-wide genetic association study (GWAS) for migraine identified 38 loci. We investigated whether 46 single-nucleotide polymorphisms (SNPs), i.e., genetic variants, at these loci may have especially pronounced, i.e., selective, association with migraine presenting with individual symptoms compared to absence of migraine. Selective genetic associations of SNPs were evaluated through a likelihood framework in the Women's Genome Health Study (WGHS), a population-based cohort of middle-aged women including 3,003 experiencing migraine and 18,108 not experiencing migraine, all with genetic information. SNPs at 12 loci displayed significant selective association for migraine subclassified by specific symptoms, among which six selective associations are novel. Symptoms showing selective association include aura, nausea/vomiting, photophobia, and phonophobia. The selective associations were consistent whether the women met all formal criteria for diagnostic for migraine or lacked one of the diagnostic criteria, formally termed probable migraine. Subsequently, we performed latent class analysis of migraine diagnostic symptoms among 69,861 women experiencing migraine from the WGHS recruitment sample to assess whether there were clusters of specific symptoms that might also have a genetic basis. However, no globally robust latent migraine substructures of diagnostic symptoms were observed nor were there selective genetic associations with specific combinations of symptoms revealed among weakly supported latent classes. The findings extend previously reported selective genetic associations with migraine diagnostic symptoms while supporting models for shared genetic susceptibility across all qualifying migraine at many loci.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.617472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907521PMC
February 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Thyroid function, sex hormones and sexual function: a Mendelian randomization study.

Eur J Epidemiol 2021 Mar 6;36(3):335-344. Epub 2021 Feb 6.

Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.

Hypothyroidism and hyperthyroidism are observationally associated with sex hormone concentrations and sexual dysfunction, but causality is unclear. We investigated whether TSH, fT4, hypo- and hyperthyroidism are causally associated with sex hormones and sexual function. We used publicly available summary statistics from genome-wide association studies on TSH and fT4 and hypo- and hyperthyroidism from the ThyroidOmics Consortium (N ≤ 54,288). Outcomes from UK Biobank (women ≤ 194,174/men ≤ 167,020) and ReproGen (women ≤ 252,514) were sex hormones (sex hormone binding globulin [SHBG], testosterone, estradiol, free androgen index [FAI]) and sexual function (ovulatory function in women: duration of menstrual period, age at menarche and menopause, reproductive lifespan, and erectile dysfunction in men). We performed two-sample Mendelian randomization (MR) analyses on summary level, and unweighted genetic risk score (GRS) analysis on individual level data. One SD increase in TSH was associated with a 1.332 nmol/L lower (95% CI: - 0.717,- 1.946; p = 2 × 10) SHBG and a 0.103 nmol/l lower (- 0.051,V0.154; p = 9 × 10) testosterone in two-sample MR, supported by the GRS approach. Genetic predisposition to hypothyroidism was associated with decreased and genetic predisposition to hyperthyroidism with increased SHBG and testosterone in both approaches. The GRS for fT4 was associated with increased testosterone and estradiol in women only. The GRS for TSH and hypothyroidism were associated with increased and the GRS for hyperthyroidism with decreased FAI in men only. While genetically predicted thyroid function was associated with sex hormones, we found no association with sexual function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10654-021-00721-zDOI Listing
March 2021

Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation.

Blood 2021 Apr;137(17):2394-2402

Aix Marseille University, INSERM, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (INRAE), Centre de Recherche en CardioVasculaire et Nutrition, Marseille, France.

Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, ∼1.2), the A1 and B haplotypes are associated with an ∼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, ∼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020008997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085481PMC
April 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Association of the Mediterranean Diet With Onset of Diabetes in the Women's Health Study.

JAMA Netw Open 2020 11 2;3(11):e2025466. Epub 2020 Nov 2.

Center for Lipid Metabolomics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: Higher Mediterranean diet (MED) intake has been associated with reduced risk of type 2 diabetes, but underlying biological mechanisms are unclear.

Objective: To characterize the relative contribution of conventional and novel biomarkers in MED-associated type 2 diabetes risk reduction in a US population.

Design, Setting, And Participants: This cohort study was conducted among 25 317 apparently healthy women. The participants with missing information regarding all traditional and novel metabolic biomarkers or those with baseline diabetes were excluded. Participants were invited for baseline assessment between September 1992 and May 1995. Data were collected from November 1992 to December 2017 and analyzed from December 2018 to December 2019.

Exposures: MED intake score (range, 0 to 9) was computed from self-reported dietary intake, representing adherence to Mediterranean diet intake.

Main Outcomes And Measures: Incident cases of type 2 diabetes, identified through annual questionnaires; reported cases were confirmed by either telephone interview or supplemental questionnaire. Proportion of reduced risk of type 2 diabetes explained by clinical risk factors and a panel of 40 biomarkers that represent different physiological pathways was estimated.

Results: The mean (SD) age of the 25 317 female participants was 52.9 (9.9) years, and they were followed up for a mean (SD) of 19.8 (5.8) years. Higher baseline MED intake (score ≥6 vs ≤3) was associated with as much as a 30% lower type 2 diabetes risk (age-adjusted and energy-adjusted hazard ratio, 0.70; 95% CI, 0.62-0.79; when regression models were additionally adjusted with body mass index [BMI]: hazard ratio, 0.85; 95% CI, 0.76-0.96). Biomarkers of insulin resistance made the largest contribution to lower risk (accounting for 65.5% of the MED-type 2 diabetes association), followed by BMI (55.5%), high-density lipoprotein measures (53.0%), and inflammation (52.5%), with lesser contributions from branched-chain amino acids (34.5%), very low-density lipoprotein measures (32.0%), low-density lipoprotein measures (31.0%), blood pressure (29.0%), and apolipoproteins (23.5%), and minimal contribution (≤2%) from hemoglobin A1c. In post hoc subgroup analyses, the inverse association of MED diet with type 2 diabetes was seen only among women who had BMI of at least 25 at baseline but not those who had BMI of less than 25 (eg, women with BMI <25, age- and energy-adjusted HR for MED score ≥6 vs ≤3, 1.01; 95% CI, 0.77-1.33; P for trend = .92; women with BMI ≥25: HR, 0.76; 95% CI, 0.67-0.87; P for trend < .001).

Conclusions And Relevance: In this cohort study, higher MED intake scores were associated with a 30% relative risk reduction in type 2 diabetes during a 20-year period, which could be explained in large part by biomarkers of insulin resistance, BMI, lipoprotein metabolism, and inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2020.25466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677766PMC
November 2020

Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

PLoS One 2020 13;15(11):e0230035. Epub 2020 Nov 13.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, United States of America.

Background: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

Methods And Results: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

Conclusion: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230035PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665790PMC
December 2020

Habitual sleep disturbances and migraine: a Mendelian randomization study.

Ann Clin Transl Neurol 2020 12 30;7(12):2370-2380. Epub 2020 Oct 30.

Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts, 02142, USA.

Objective: Sleep disturbances are associated with increased risk of migraine, however the extent of shared underlying biology and the direction of causal relationships between these traits is unclear. Delineating causality between sleep patterns and migraine may offer new pathophysiologic insights and inform subsequent intervention studies. Here, we used genetic approaches to test for shared genetic influences between sleep patterns and migraine, and to test whether habitual sleep patterns may be causal risk factors for migraine and vice versa.

Methods: To quantify genetic overlap, we performed genome-wide genetic correlation analyses using genome-wide association studies of nine sleep traits in the UK Biobank (n ≥ 237,627), and migraine from the International Headache Genetics Consortium (59,674 cases and 316,078 controls). We then tested for potential causal effects between sleep traits and migraine using bidirectional, two-sample Mendelian randomization.

Results: Seven sleep traits demonstrated genetic overlap with migraine, including insomnia symptoms (rg = 0.29, P < 10 ) and difficulty awakening (rg = 0.11, P < 10 ). Mendelian randomization analyses provided evidence for potential causal effects of difficulty awakening on risk of migraine (OR [95% CI] = 1.37 [1.12-1.68], P = 0.002), and nominal evidence that liability to insomnia symptoms increased the risk of migraine (1.09 [1.02-1.16], P = 0.02). In contrast, there was minimal evidence for an effect of migraine liability on sleep patterns or disturbances.

Interpretation: These data support a shared genetic basis between several sleep traits and migraine, and support potential causal effects of difficulty awakening and insomnia symptoms on migraine risk. Treatment of sleep disturbances may therefore be a promising clinical intervention in the management of migraine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.51228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732254PMC
December 2020

Effect of Vitamin D and ω-3 Fatty Acid Supplementation on Risk of Age-Related Macular Degeneration: An Ancillary Study of the VITAL Randomized Clinical Trial.

JAMA Ophthalmol 2020 12;138(12):1280-1289

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: Observational studies suggest that higher intake or blood levels of vitamin D and marine ω-3 fatty acids may be associated with lower risks of age-related macular degeneration (AMD). However, evidence from randomized trials is limited.

Objective: To evaluate whether daily supplementation with vitamin D3, marine ω-3 fatty acids, or both prevents the development or progression of AMD.

Design, Setting, And Participants: This was a prespecified ancillary study of the Vitamin D and Omega-3 Trial (VITAL), a nationwide, placebo-controlled, 2 × 2 factorial design randomized clinical trial of supplementation with vitamin D and marine ω-3 fatty acids for the primary prevention of cancer and cardiovascular disease. Participants included 25 871 men and women in the US. Randomization was from November 2011 to March 2014, and study pill-taking ended as planned on December 31, 2017.

Interventions: Vitamin D3 (cholecalciferol), 2000 IU per day, and marine ω-3 fatty acids, 1 g per day.

Main Outcomes And Measures: The primary end point was total AMD events, a composite of incident cases of AMD plus cases of progression to advanced AMD among participants with AMD at baseline, based on self-report confirmed by medical record review. Analyses were conducted using the intention-to-treat population.

Results: In total, 25 871 participants with a mean (SD) age of 67.1 (7.0) years were included in the trial. Of them, 50.6% were women, 71.3% were self-declared non-Hispanic White participants, and 20.2% were Black participants. During a median (range) of 5.3 (3.8-6.1) years of treatment and follow-up, 324 participants experienced an AMD event (285 incident AMD and 39 progression to advanced AMD). For vitamin D3, there were 163 events in the treated group and 161 in the placebo group (hazard ratio [HR], 1.02; 95% CI, 0.82-1.27). For ω-3 fatty acids, there were 157 events in the treated group and 167 in the placebo group (HR, 0.94; 95% CI, 0.76-1.17). In analyses of individual components for the primary end point, HRs comparing vitamin D3 groups were 1.09 (95% CI, 0.86-1.37) for incident AMD and 0.63 (95% CI, 0.33-1.21) for AMD progression. For ω-3 fatty acids, HRs were 0.93 (95% CI, 0.73-1.17) for incident AMD and 1.05 (95% CI, 0.56-1.97) for AMD progression.

Conclusion And Relevance: Neither vitamin D3 nor marine ω-3 fatty acid supplementation had a significant overall effect on AMD incidence or progression.

Trial Registration: ClinicalTrials.gov Identifier: NCT01782352.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2020.4409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596682PMC
December 2020

Circulating branched-chain amino acids and long-term risk of obesity-related cancers in women.

Sci Rep 2020 10 6;10(1):16534. Epub 2020 Oct 6.

Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 900 Commonwealth Avenue, Boston, MA, 02215, USA.

Obesity is a risk factor for > 13 cancer sites, although it is unknown whether there is a common mechanism across sites. Evidence suggests a role for impaired branched-chain amino acid (BCAAs; isoleucine, leucine, valine) metabolism in obesity, insulin resistance, and immunity; thus, we hypothesized circulating BCAAs may be associated with incident obesity-related cancers. We analyzed participants in the prospective Women's Health Study without a history of cancer at baseline blood collection (N = 26,711, mean age = 54.6 years [SD = 7.1]). BCAAs were quantified via NMR spectroscopy, log-transformed, and standardized. We used Cox proportional regression models adjusted for age, race, smoking, diet, alcohol, physical activity, menopausal hormone use, Body Mass Index (BMI), diabetes, and other risk factors. The endpoint was a composite of obesity-related cancers, defined per the International Agency for Research on Cancer 2016 report, over a median 24 years follow-up. Baseline BMI ≥ 30 kg/m compared with BMI 18.5-25.0 kg/m was associated with 23% greater risk of obesity-related cancers (n = 2751 events; multivariable HR 1.23, 95% CI 1.11-1.37). However, BCAAs were not associated with obesity-related cancers (multivariable HR per SD = 1.01 [0.97-1.05]). Results for individual BCAA metabolites suggested a modest association for leucine with obesity-related cancers (1.04 [1.00-1.08]), and no association for isoleucine or valine (0.99 [0.95-1.03] and 1.00 [0.96-1.04], respectively). Exploratory analyses of BCAAs with individual sites included positive associations between leucine and postmenopausal breast cancer, and isoleucine with pancreatic cancer. Total circulating BCAAs were unrelated to obesity-related cancer incidence although an association was observed for leucine with incident obesity-related cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-73499-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539150PMC
October 2020

Genome-wide association study identifies 48 common genetic variants associated with handedness.

Nat Hum Behav 2021 01 28;5(1):59-70. Epub 2020 Sep 28.

Institute of Biological Psychiatry, Mental Health Services of Copenhagen, Copenhagen, Denmark.

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (r = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41562-020-00956-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116623PMC
January 2021

Genetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality.

Hum Genet 2021 Mar 21;140(3):529-552. Epub 2020 Sep 21.

School of Biomedical Sciences, Faculty of Health, and Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, QLD, Australia.

Evidence from observational studies indicates that endometriosis and depression often co-occur. However, conflicting evidence exists, and the etiology as well as biological mechanisms underlying their comorbidity remain unknown. Utilizing genome-wide association study (GWAS) data, we comprehensively assessed the relationship between endometriosis and depression. Single nucleotide polymorphism effect concordance analysis (SECA) found a significant genetic overlap between endometriosis and depression (P = 9.99 × 10). Linkage disequilibrium score regression (LDSC) analysis estimated a positive and highly significant genetic correlation between the two traits (r = 0.27, P = 8.85 × 10). A meta-analysis of endometriosis and depression GWAS (sample size = 709,111), identified 20 independent genome-wide significant loci (P < 5 × 10), of which eight are novel. Mendelian randomization analysis (MR) suggests a causal effect of depression on endometriosis. Combining gene-based association results across endometriosis and depression GWAS, we identified 22 genes with a genome-wide significant Fisher's combined P value (FCP < 2.75 × 10). Genes with a nominal gene-based association (P < 0.05) were significantly enriched across endometriosis and depression (P = 2.90 × 10). Also, genes overlapping the two traits at P < 0.1 (P = 1.31 × 10) were significantly enriched for the biological pathways 'cell-cell adhesion', 'inositol phosphate metabolism', 'Hippo-Merlin signaling dysregulation' and 'gastric mucosa abnormality'. These results reveal a shared genetic etiology for endometriosis and depression. Indeed, additional analyses found evidence of a causal association between each of endometriosis and depression and at least one abnormal condition of gastric mucosa. Our study confirms the comorbidity of endometriosis and depression, implicates links with gastric mucosa abnormalities in their causal pathways and reveals potential therapeutic targets for further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-020-02223-6DOI Listing
March 2021

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Diabetes 2020 12 11;69(12):2806-2818. Epub 2020 Sep 11.

Department of Biostatistics, Boston University School of Public Health, Boston, MA.

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , , , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry ( = 2 × 10, = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db20-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679778PMC
December 2020

Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria.

Genet Med 2021 01 2;23(1):140-148. Epub 2020 Sep 2.

Deparment of Medicine, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA.

Purpose: Erythropoietic protoporphyria (EPP), characterized by painful cutaneous photosensitivity, results from pathogenic variants in ferrochelatase (FECH). For 96% of patients, EPP results from coinheriting a rare pathogenic variant in trans of a common hypomorphic variant c.315-48T>C (minor allele frequency 0.05). The estimated prevalence of EPP derived from the number of diagnosed individuals in Europe is 0.00092%, but this may be conservative due to underdiagnosis. No study has estimated EPP prevalence using large genetic data sets.

Methods: Disease-associated FECH variants were identified in the UK Biobank, a data set of 500,953 individuals including 49,960 exome sequences. EPP prevalence was then estimated. The association of FECH variants with EPP-related traits was assessed.

Results: Analysis of pathogenic FECH variants in the UK Biobank provides evidence that EPP prevalence is 0.0059% (95% confidence interval [CI]: 0.0042-0.0076%), 1.7-3.0 times more common than previously thought in the UK. In homozygotes for the common c.315-48T>C FECH variant, there was a novel decrement in both erythrocyte mean corpuscular volume (MCV) and hemoglobin.

Conclusion: The prevalence of EPP has been underestimated secondary to underdiagnosis. The common c.315-48T>C allele is associated with both MCV and hemoglobin, an association that could be important both for those with and without EPP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-00951-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796935PMC
January 2021

A genome-wide cross-phenotype meta-analysis of the association of blood pressure with migraine.

Nat Commun 2020 07 6;11(1):3368. Epub 2020 Jul 6.

Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.

Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine (N/N = 59,674/316,078) and BP (N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, r = 0.11, P = 3.56 × 10) and systolic BP (SBP, r = 0.06, P = 0.01), but not pulse pressure (PP, r = -0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci (P ≤ 5 × 10), nine of which replicate (P < 0.05) in the UK Biobank. Five shared loci (ITGB5, SMG6, ADRA2B, ANKDD1B, and KIAA0040) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15-1.25]/10 mmHg; P = 5.57 × 10) on migraine than SBP (1.05 [1.03-1.07]/10 mmHg; P = 2.60 × 10) and a corresponding opposite effect for PP (0.92 [0.88-0.95]/10 mmHg; P = 3.65 × 10). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17002-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338361PMC
July 2020

Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.

Circ Genom Precis Med 2020 08 8;13(4):e002772. Epub 2020 Jun 8.

Department of Epidemiology, School of Public Health (L.F.B., J.A.S., W.Z., S.L.R.K.), University of Michigan, Ann Arbor, MI.

Background: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

Methods: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

Results: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in .

Conclusions: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.119.002772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442680PMC
August 2020

Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.

Eur J Epidemiol 2020 Jul 7;35(7):685-697. Epub 2020 May 7.

Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, 21741, Malmö, Sweden.

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10654-020-00638-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867117PMC
July 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2020 May 5. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
May 2020

Pleiotropy-Based Decomposition of Genetic Risk Scores: Association and Interaction Analysis for Type 2 Diabetes and CAD.

Am J Hum Genet 2020 05 16;106(5):646-658. Epub 2020 Apr 16.

Harvard Medical School, Boston, MA 02115, USA; Medical and Population Genetics Program, Broad Institute, Cambridge, MA 02142, USA; Massachusetts General Hospital, Boston, MA 02114, USA.

Genetic risk for a disease in the population may be represented as a genetic risk score (GRS) constructed as the sum of inherited risk alleles, weighted by allelic effects established in an independent population. While this formulation captures overall genetic risk, it typically does not address risk due to specific biological mechanisms or pathways that may nevertheless be important for interpretation or treatment response. Here, a GRS for disease is resolved into independent or nearly independent components pertaining to biological mechanisms inferred from pleiotropic relationships. The component GRSs' weights are derived from the singular value decomposition (SVD) of the matrix of appropriately scaled genetic effects, i.e., beta coefficients, of the disease variants across a panel of the disease-related phenotypes. The SVD-based formalism also associates combinations of disease-related phenotypes with inferred disease pathways. Applied to incident type 2 diabetes (T2D) in the Women's Genome Health Study (N = 23,294), component GRSs discriminate glycemic control and lipid-based genetic risk, while revealing significant interactions between specific components and BMI or physical activity, the latter not observed with a GRS for overall T2D genetic liability. Applied to coronary artery disease (CAD) in both the WGHS and in JUPITER (N = 8,749), a randomized trial of rosuvastatin for primary prevention of CVD, component GRSs discriminate genetic risk associated with LDL-C from risk associated with reciprocal genetic effects on triglycerides and HDL-C. They also inform the pharmacogenetics of statin treatment by demonstrating that benefit from rosuvastatin is as strongly related to genetic risk from triglycerides and HDL-C as from LDL-C.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212269PMC
May 2020

Effect of genetic liability to migraine on cognition and brain volume: A Mendelian randomization study.

Cephalalgia 2020 08 4;40(9):998-1002. Epub 2020 Apr 4.

Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Objective: To investigate potential causality between genetic liability to migraine and Alzheimer's disease, intelligence, and brain volume using two-sample Mendelian randomization.

Methods: The exposure consisted of independent genetic variants associated with migraine in the largest (59,674 cases/316,078 controls) published genome-wide association study. Outcomes included Alzheimer's disease (71,880 cases/383,378 controls), a measure of general intelligence (n = 269,867), intracranial volume (n = 11,373), and seven subcortical brain volumes (n ∼ 13,000), all with available genome-wide association study summary statistics. Mendelian randomization effects were estimated using inverse-variance weighted analysis.

Results: Genetic liability to migraine did not associate with Alzheimer's disease (odds ratio [95% confidence interval] 1.01 [1.00-1.02],  = 0.07), intelligence (standardized beta [95% confidence interval] 0.01 [0.00-0.02],  = 0.13), or any brain volume measures (all  > 0.05). No individual migraine variant associated with any of the outcomes at genome-wide significance.

Conclusions: These data do not support a causal effect of migraine liability on Alzheimer's disease, intelligence, or brain volume.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0333102420916751DOI Listing
August 2020

Could vitamin D reduce obesity-associated inflammation? Observational and Mendelian randomization study.

Am J Clin Nutr 2020 05;111(5):1036-1047

Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.

Background: Obesity is associated with inflammation but the role of vitamin D in this process is not clear.

Objectives: We aimed to assess the associations between serum 25-hydroxyvitamin D [25(OH)D], BMI, and 16 inflammatory biomarkers, and to assess the role of vitamin D as a potential mediator in the association between higher BMI and inflammation.

Methods: Northern Finland Birth Cohort 1966 (NFBC1966) 31-y data on 3586 individuals were analyzed to examine the observational associations between BMI, 25(OH)D, and 16 inflammatory biomarkers. Multivariable regression analyses and 2-sample regression-based Mendelian randomization (MR) mediation analysis were performed to assess any role of vitamin D in mediating a causal effect of BMI on inflammatory biomarkers [soluble intercellular adhesion molecule 1 (sICAM-1), high sensitivity C-reactive protein (hs-CRP), and α1-acid glycoprotein (AGP)] for which observational associations were detected. For MR, genome-wide association study summary results ranging from 5163 to 806,834 individuals were used for biomarkers, 25(OH)D, and BMI. Findings were triangulated with a literature review of vitamin D supplementation trials.

Results: In NFBC1966, mean BMI (kg/m2) was 24.8 (95% CI: 24.7, 25.0) and mean 25(OH)D was 50.3 nmol/L (95% CI: 49.8, 50.7 nmol/L). Inflammatory biomarkers correlated as 4 independent clusters: interleukins, adhesion molecules, acute-phase proteins, and chemokines. BMI was positively associated with 9 inflammatory biomarkers and inversely with 25(OH)D (false discovery rate < 0.05). 25(OH)D was inversely associated with sICAM-1, hs-CRP, and AGP, which were positively associated with BMI. The MR analyses showed causal association of BMI on these 3 inflammatory biomarkers. There was no observational or MR evidence that circulating 25(OH)D concentrations mediated the association between BMI and these 3 inflammatory markers. Review of randomized controlled trials (RCTs) supported our findings showing no impact of vitamin D supplementation on inflammatory biomarkers.

Conclusions: The findings from our observational study and causal MR analyses, together with data from RCTs, do not support a beneficial role of vitamin D supplementation on obesity-related inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/nqaa056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198294PMC
May 2020