Publications by authors named "Harold Snieder"

380 Publications

Twenty-Five Novel Loci for Carotid Intima-Media Thickness: A Genome-Wide Association Study in >45 000 Individuals and Meta-Analysis of >100 000 Individuals.

Arterioscler Thromb Vasc Biol 2021 Dec 2:ATVBAHA121317007. Epub 2021 Dec 2.

Department of Cardiology, University of Groningen, University Medical Center Groningen, the Netherlands. (M.W.Y., S.W., Y.J.v.d.V., N.V., M.A.S., P.v.d.H.).

Objective: Carotid artery intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. Twenty susceptibility loci for cIMT were previously identified and the identification of additional susceptibility loci furthers our knowledge on the genetic architecture underlying atherosclerosis. Approach and Results: We performed 3 genome-wide association studies in 45 185 participants from the UK Biobank study who underwent cIMT measurements and had data on minimum, mean, and maximum thickness. We replicated 15 known loci and identified 20 novel loci associated with cIMT at <5×10. Seven novel loci (, AD, , , , matrix metalloproteinase [], and ) were identified in all 3 phenotypes. An additional new locus () was identified in the meta-analysis of the 3 phenotypes. Sex interaction analysis revealed sex differences in 7 loci including a novel locus () in males. Meta-analysis of UK Biobank data with a previous meta-analysis led to identification of three novel loci (). Transcriptome-wide association analyses implicated additional genes , , and . Gene set analysis showed an enrichment in extracellular organization and the PDGF (platelet-derived growth factor) signaling pathway. We found positive genetic correlations of cIMT with coronary artery disease =0.21 (=1.4×10), peripheral artery disease =0.45 (=5.3×10), and systolic blood pressure =0.30 (=4.0×10). A negative genetic correlation between average of maximum cIMT and high-density lipoprotein was found =-0.12 (=7.0×10).

Conclusions: Genome-wide association meta-analyses in >100 000 individuals identified 25 novel loci associated with cIMT providing insights into genes and tissue-specific regulatory mechanisms of proatherosclerotic processes. We found evidence for shared biological mechanisms with cardiovascular diseases.
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http://dx.doi.org/10.1161/ATVBAHA.121.317007DOI Listing
December 2021

The vision-related burden of dry eye.

Ocul Surf 2021 Oct 28. Epub 2021 Oct 28.

Department of Ophthalmology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Postbus 30.001, Groningen, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Postbus 30.001, Groningen, the Netherlands; Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Hospital, Lambeth Palace Road, Waterloo, London, SE1 7EH, United Kingdom; Department of Ophthalmology, Vestfold Hospital Trust, Tønsberg, Norway. Electronic address:

Purpose: To investigate the relationship between dry eye disease (DED) and vision-related quality of life (VR-QoL) at population level.

Methods: DED and VR-QoL were assessed in 89,022 participants (18-96 years, 59% female) from the Dutch population-based Lifelines cohort using the Women's Health study (WHS) and Visual function 25 (VFQ25) questionnaires. The relationship between DED and compromised VR-QoL was assessed with logistic regression, corrected for age, sex, BMI, income, education, smoking, and 55 comorbidities.

Results: 9.1% of participants had DED. The participants with DED had higher risk of compromised average of ten domains of VR-QoL (OR 3.12 (95% CI 2.98-3.27) corrected for age, sex, BMI, income, smoking, and 55 comorbidities). Increasing symptom frequency was highly associated with decreasing VR-QoL (P < 0.0005). In all VR-QoL domains, including measures of daily visual function and emotional well-being, DED was clearly associated with compromised VR-QoL. Compared to macular degeneration, glaucoma, retinal detachment, and allergic conjunctivitis, DED presented similar or higher risks for compromised score on all VR-QoL domains. The population-attributable fraction of DED for compromised general vision exceeded that of other eye diseases investigated, especially in the younger age groups.

Conclusion: DED is associated with reductions in all domains of VR-QoL, also after correction for associated comorbidities. We found that DED imposes an extensive population burden regarding compromised VR-QoL due to its high prevalence and substantial impact on VR-QoL, higher than that for other common vision-affecting eye disorders. Our results emphasize the importance of recognizing DED as a serious disorder from both patient and public health perspectives.
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http://dx.doi.org/10.1016/j.jtos.2021.10.007DOI Listing
October 2021

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

HGG Adv 2021 Jan 31;2(1). Epub 2020 Oct 31.

Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17489, Germany.

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.
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http://dx.doi.org/10.1016/j.xhgg.2020.100013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562625PMC
January 2021

Diurnal Cortisol Slope and Nighttime Blood Pressure: A Study in European Americans and African Americans.

Ethn Dis 2021 21;31(4):481-488. Epub 2021 Oct 21.

Georgia Prevention Institute, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA.

Objectives: African Americans (AAs) have higher nighttime blood pressure (BP) than European Americans (EAs). Stress has been suggested to play a role in this difference, but the mechanism is not well-understood. Flatter diurnal cortisol slope (DCS) is a well-known biological marker of stress. The objectives of this study were to: 1) examine ethnic differences in DCS; 2) evaluate the association between DCS and nighttime BP; and 3) determine the extent to which ethnic differences in nighttime BP can be explained by ethnic differences in DCS.

Methods: A total of 510 participants (age range: 14-35 years; 49.6% AAs, 54.5% females) provided four salivary cortisol samples at bedtime, wakeup, 30-minutes post-wakeup, and 60-minutes post-wakeup. Additionally, participants wore an ambulatory BP monitor for 24 hours. DCS was calculated as the average of the three morning samples minus the bedtime measurement.

Results: After adjustment for age, sex, BMI, and smoking, AAs had blunted DCS (P=.018) and higher nighttime systolic BP (SBP) and diastolic BP (DBP) (Ps<.001) compared with EAs. The DCS was inversely related to nighttime SBP and this relationship did not depend on ethnicity. The ethnic difference of nighttime SBP was significantly attenuated upon addition of DCS to the model. Mediation test showed that 9.5% of ethnic difference in nighttime SBP could be explained by DCS (P=.039).

Conclusion: This study confirms ethnic differences in DCS and nighttime BP and further demonstrates that the ethnic differences in DCS can, at least partially, explain the ethnic differences found in nighttime BP.
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http://dx.doi.org/10.18865/ed.31.4.481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545480PMC
October 2021

Spousal similarities in cardiometabolic risk factors: A cross-sectional comparison between Dutch and Japanese data from two large biobank studies.

Atherosclerosis 2021 10 26;334:85-92. Epub 2021 Aug 26.

Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan; Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Disaster Public Health, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan.

Background And Aims: Few studies have examined and compared spousal concordance in different populations. This study aimed to quantify and compare spousal similarities in cardiometabolic risk factors and diseases between Dutch and Japanese populations.

Methods: This cross-sectional study included 28,265 Dutch Lifelines Cohort Study spouse pairs (2006-2013) and 5,391 Japanese Tohoku Medical Megabank Organization (ToMMo) Cohort Study pairs (2013-2016). Spousal similarities in cardiometabolic risk factors were evaluated using Pearson's correlation or logistic regression analyses adjusted for spousal age.

Results: The husbands' and wives' average ages in the Lifelines and ToMMo cohorts were 50.0 and 47.7 years and 63.2 and 60.4 years, respectively. Significant spousal similarities occurred with all cardiometabolic risk factors and diseases of interest in both cohorts. The age-adjusted correlation coefficients ranged from 0.032 to 0.263, with the strongest correlations observed in anthropometric traits. Spousal odds ratios [95% confidence interval] for the Lifelines vs. ToMMo cohort ranged from 1.45 (1.36-1.55) vs. 1.20 (1.05-1.38) for hypertension to 6.86 (6.30-7.48) vs. 4.60 (3.52-6.02) for current smoking. An increasing trend in spousal concordance with age was observed for sufficient physical activity in both cohorts. For current smoking, those aged 20-39 years showed the strongest concordance between pairs in both cohorts. The Dutch pairs showed stronger similarities in anthropometric traits and lifestyle habits (smoking and drinking) than their Japanese counterparts.

Conclusions: Spouses showed similarities in several cardiometabolic risk factors among Dutch and Japanese populations, with regional and cultural influences on spousal similarities.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.08.037DOI Listing
October 2021

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

Genes (Basel) 2021 07 29;12(8). Epub 2021 Jul 29.

Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

SGLT2 inhibitors (SGLT2i) block renal glucose reabsorption. Due to the unexpected beneficial observations in type 2 diabetic patients potentially related to increased natriuresis, SGLT2i are also studied for heart failure treatment. This study aimed to identify genetic variants mimicking SGLT2i to further our understanding of the potential underlying biological mechanisms. Using the UK Biobank resource, we identified 264 SNPs located in the gene or within 25kb of the 5' and 3' flanking regions, of which 91 had minor allele frequencies >1%. Twenty-seven SNPs were associated with glycated hemoglobin (HbA1c) after Bonferroni correction in participants without diabetes, while none of the SNPs were associated with sodium excretion. We investigated whether these variants had a directionally consistent effect on sodium excretion, HbA1c levels, and expression. None of the variants met these criteria. Likewise, we identified no common missense variants, and although four SNPs could be defined as 5' or 3' prime untranslated region variants of which rs45612043 was predicted to be deleterious, these SNPs were not annotated to . In conclusion, no genetic variant was found mimicking SGLT2i based on their location near and their association with sodium excretion or HbA1c and expression or function.
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http://dx.doi.org/10.3390/genes12081174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391850PMC
July 2021

Genome-wide CNV investigation suggests a role for cadherin, Wnt, and p53 pathways in primary open-angle glaucoma.

BMC Genomics 2021 Aug 4;22(1):590. Epub 2021 Aug 4.

Departments of Clinical Genetics and Ophthalmology, Amsterdam University Medical Center (AMC), Location AMC K2-217 | AMC-UvA, P.O.Box 22700, 1100 DE, Amsterdam, The Netherlands.

Background: To investigate whether copy number variations (CNVs) are implicated in molecular mechanisms underlying primary open-angle glaucoma (POAG), we used genotype data of POAG individuals and healthy controls from two case-control studies, AGS (n = 278) and GLGS-UGLI (n = 1292). PennCNV, QuantiSNP, and cnvPartition programs were used to detect CNV. Stringent quality controls at both sample and marker levels were applied. The identified CNVs were intersected in CNV region (CNVR). After, we performed burden analysis, CNV-genome-wide association analysis, gene set overrepresentation and pathway analysis. In addition, in human eye tissues we assessed the expression of the genes lying within significant CNVRs.

Results: We reported a statistically significant greater burden of CNVs in POAG cases compared to controls (p-value = 0,007). In common between the two cohorts, CNV-association analysis identified statistically significant CNVRs associated with POAG that span 11 genes (APC, BRCA2, COL3A1, HLA-DRB1, HLA-DRB5, HLA-DRB6, MFSD8, NIPBL, SCN1A, SDHB, and ZDHHC11). Functional annotation and pathway analysis suggested the involvement of cadherin, Wnt signalling, and p53 pathways.

Conclusions: Our data suggest that CNVs may have a role in the susceptibility of POAG and they can reveal more information on the mechanism behind this disease. Additional genetic and functional studies are warranted to ascertain the contribution of CNVs in POAG.
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http://dx.doi.org/10.1186/s12864-021-07846-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336345PMC
August 2021

Genetic association study of childhood aggression across raters, instruments, and age.

Transl Psychiatry 2021 07 30;11(1):413. Epub 2021 Jul 30.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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http://dx.doi.org/10.1038/s41398-021-01480-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324785PMC
July 2021

Spontaneous baroreflex sensitivity and its association with age, sex, obesity indices and hypertension: a population study.

Am J Hypertens 2021 Jul 30. Epub 2021 Jul 30.

University of Groningen, University Medical Center Groningen, Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion regulation, The Netherlands.

Background: Low baroreflex sensitivity (BRS) is an established risk factor for cardiovascular disorders. We investigated determinants of BRS in a large sample from general population.

Methods: In a population-based study (n=901) data were collected on BRS, arm cuff blood pressure (BP) and obesity indices including body mass index (BMI), waist-to-hip ratio (WHR), waist circumference and percentage body fat (%BF). BRS was calculated by spectral analysis software based on continuously recorded spontaneous fluctuations in beat-to-beat finger BP for 10 to 15 minutes. Correlations and multivariable regression analyses were used to test associations of age, sex, obesity indices and hypertension with BRS while considering effects of lifestyle factors (smoking, alcohol consumption and physical activity).

Results: In multivariable analysis, age, sex, %BF, and hypertension were independently associated with BRS. BRS decreased with -0.10 (95% confidence interval [CI]: -0.15 to -0.06) ms/mmHg with each year of increase in age. Women had -1.55 (95% CI: -2.28 to -0.73) ms/mmHg lower mean BRS than men. The effects of %BF (per 10% increase) and hypertension on BRS were -0.55 (95% CI: -0.97 to -0.13) ms/mmHg and -1.23 (95% CI: -1.92 to -0.46) ms/mmHg, respectively. There was no evidence of associations between BRS and lifestyle factors. Age, age 2, sex, and their interactions plus %BF and hypertension contributed 16.9% of total variance of BRS.

Conclusions: In this large general population study, we confirm prior findings that age and sex are important factors associated with BRS and find %BF is more strongly related to less favorable BRS levels than BMI.
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http://dx.doi.org/10.1093/ajh/hpab122DOI Listing
July 2021

Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour.

Nat Hum Behav 2021 Jul 1. Epub 2021 Jul 1.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.
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http://dx.doi.org/10.1038/s41562-021-01135-3DOI Listing
July 2021

Medication use and dry eye symptoms: A large, hypothesis-free, population-based study in the Netherlands.

Ocul Surf 2021 Oct 23;22:1-12. Epub 2021 Jun 23.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Postbus 30.001, Groningen, the Netherlands; Department of Twin Research & Genetic Epidemiology, The School of Life Course Sciences, King's College London, London, SE1 7EH, United Kingdom. Electronic address:

Purpose: To date, population-based studies reporting associations between dry eye disease and medications were hypothesis-driven, did not take into account underlying comorbidities, and did not investigate individual drugs. The purpose of this study was to clarify the association of dry eye symptoms with medication classes and individual drugs, using a hypothesis-free approach.

Methods: 79,606 participants (age 20-97 years, 59.2% female) from the population-based Lifelines cohort in the Netherlands were cross-sectionally assessed for dry eye symptoms using the Womens' Health Study dry eye questionnaire. All medications used were coded with the ATC classification system. Logistic regression was used to assess the risk of the 59 most-used therapeutic/pharmacological subgroups and the 99 most-used individual drugs (all n > 200) on dry eye symptoms, correcting for age, sex, body mass index, and 48 comorbidities associated with dry eye.

Results: Thirty-eight (64%) medication subgroups and fifty-two (53%) individual drugs were associated with dry eye symptoms (P < 0.05), after correction for age and sex only. A multivariable model correcting for comorbidities revealed highly significant associations between dry eye symptoms and drugs for peptic ulcer (particularly proton pump inhibitors (PPIs)), antiglaucoma and anticholinergic medications.

Conclusions: This study underlines that medication use is highly informative of risk of dry eye symptoms. Correction for underlying comorbidities is critical to avoid confounding effects. This study confirms suggested associations between medications and dry eye symptoms at a population level and shows several new associations. The novel link between PPIs and dry eye symptoms deserves particular attention given how commonly they are prescribed.
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http://dx.doi.org/10.1016/j.jtos.2021.06.009DOI Listing
October 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.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

The physical and mental burden of dry eye disease: A large population-based study investigating the relationship with health-related quality of life and its determinants.

Ocul Surf 2021 07 24;21:107-117. Epub 2021 May 24.

Department of Ophthalmology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Postbus 30.001, Groningen, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Postbus 30.001, Groningen, the Netherlands; Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Hospital, Lambeth Palace Road, Waterloo, London, SE1 7EH, United Kingdom. Electronic address:

Purpose: This large cross-sectional population-based study investigated the relationship between dry eye disease (DED) and health-related quality of life (HR-QoL).

Methods: Dry eye and HR-QoL were assessed in 78,165 participants (19-94 yrs, 59.2% female) from the Dutch population-based Lifelines cohort, using the WHS and the SF36 questionnaire, respectively. Logistic regression was used to assess the relationship between DED and below median Physical Component Summary (PCS) and Mental Component Summary (MCS) score, corrected for age, sex, education, BMI, and 52 comorbidities.

Results: Overall, 8.9% of participants had DED. Participants with DED had an increased risk of low PCS (OR 1.54 (95% CI 1.46-1.62)) and MCS scores (OR 1.39 (95% CI 1.32-1.46)), corrected for age and sex. This risk remained significant after correction for comorbidities (P < 0.0005). Increasing DED symptom frequency was associated with decreasing HR-QoL (P < 0.0005). Undiagnosed DED subjects had a significantly increased risk of low mental HR-QoL with increasing dry eye symptoms compared to diagnosed subjects (P < 0.0005). Compared to allergic conjunctivitis, glaucoma, macular degeneration and retinal detachment, DED showed the highest risk of low HR-QoL. Compared to other common systemic and chronic disorders, such as depression, rheumatoid arthritis, and COPD, DED was distinctive by having a substantial reduction in both PCS and MCS.

Conclusion: DED is associated with substantial reductions in both physical and mental HR-QoL, also after correction for associated comorbidities. Not having a diagnosis is associated with worse mental HR-QoL in subjects with severe DED. Our results underline the importance of recognizing dry eye as a serious disorder.
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http://dx.doi.org/10.1016/j.jtos.2021.05.006DOI Listing
July 2021

The relationship between alcohol consumption and dry eye.

Ocul Surf 2021 07 21;21:87-95. Epub 2021 May 21.

Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Hospital, Lambeth Palace Road, Waterloo, London, SE1 7EH, United Kingdom; Dutch Dry Eye Clinic, Emmastraat 21, 6881SN, Velp, the Netherlands; Departments of Ophthalmology and Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Postbus 30.001, Groningen, the Netherlands. Electronic address:

Purpose: To assess the association between dry eye disease (DED) and alcohol consumption using a large population-based cohort.

Methods: 77,145 participants (19-94 years, 59% female) from the Dutch Lifelines cohort were cross-sectionally assessed for DED using the Women's Health Study (WHS) dry eye questionnaire. Alcohol intake was assessed using self-reported food frequency questionnaires. The relationship between DED and alcohol use was analyzed using logistic regression, corrected for age, sex, BMI, smoking status, education, income, and 55 potentially confounding comorbidities.

Results: Overall, 30.0% of participants had symptomatic dry eye. Alcohol use significantly increased the risk of symptomatic dry eye in females (odds ratio [OR] 1.095, 95%CI 1.045-1.148), but not in males (OR 0.988, 95%CI 0.900-1.084). Contrarily, in male drinkers, increasing alcohol intake (in 10 g/day) had a protective effect on symptomatic dry eye (OR 0.962, 95%CI 0.934-0.992), which was not seen in females (OR 0.986, 95%CI 0.950-1.023). Alcohol use and intake had a sex-specific effect on all outcomes of DED assessed: symptomatic dry eye, highly symptomatic dry eye, clinical diagnosis, and WHS definition dry eye.

Conclusions: This large population-based study found alcohol use to have a clear sex-specific effect on DED, presenting as a risk-factor only in females. This adds to the evidence of sex-specific pathophysiological mechanisms of dry eye and illustrates the importance of sex stratification in studies investigating DED. The mild protective effect of increased alcohol intake in male drinkers is advised to be interpreted with caution, as alcohol's other health effects might be of greater clinical significance.
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http://dx.doi.org/10.1016/j.jtos.2021.05.005DOI Listing
July 2021

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

Nat Commun 2021 05 10;12(1):2579. Epub 2021 May 10.

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

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-021-22338-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110798PMC
May 2021

Advances in Genomic Discovery and Implications for Personalized Prevention and Medicine: Estonia as Example.

J Pers Med 2021 Apr 29;11(5). Epub 2021 Apr 29.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

The current paradigm of personalized medicine envisages the use of genomic data to provide predictive information on the health course of an individual with the aim of prevention and individualized care. However, substantial efforts are required to realize the concept: enhanced genetic discoveries, translation into intervention strategies, and a systematic implementation in healthcare. Here we review how further genetic discoveries are improving personalized prediction and advance functional insights into the link between genetics and disease. In the second part we give our perspective on the way these advances in genomic research will transform the future of personalized prevention and medicine using Estonia as a primer.
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http://dx.doi.org/10.3390/jpm11050358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145318PMC
April 2021

Decreased heritability and emergence of novel genetic effects on pulse wave velocity from youth to young adulthood.

Sci Rep 2021 04 26;11(1):8911. Epub 2021 Apr 26.

Department of Medicine, Georgia Prevention Institution (GPI), Medical College of Georgia, Augusta University, Building HS-1640, Augusta, GA, 30912, USA.

Increased arterial stiffness measured by pulse wave velocity (PWV) is an important parameter in the assessment of cardiovascular risk. Our previous longitudinal study has demonstrated that carotid-distal PWV showed reasonable stability throughout youth and young adulthood. This stability might be driven by genetic factors that are expressed consistently over time. We aimed to illustrate the relative contributions of genetic and environmental factors to the stability of carotid-distal PWV from youth to young adulthood. We also examined potential ethnic differences. For this purpose, carotid-distal PWV was measured twice in 497 European American (EA) and African American (AA) twins, with an average interval time of 3 years. Twin modelling on PWV showed that heritability decreased over time (62-35%), with the nonshared environmental influences becoming larger. There was no correlation between the nonshared environmental factors on PWV measured at visit 1 and visit 2, with the phenotypic tracking correlation (r = 0.32) completely explained by shared genetic factors over time. Novel genetic influences were identified accounting for a significant part of the variance (19%) at the second measurement occasion. There was no evidence for ethnic differences. In summary, novel genetic effects appear during development into young adulthood and account for a considerable part of the variation in PWV. Environmental influences become larger with age for PWV.
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http://dx.doi.org/10.1038/s41598-021-88490-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076172PMC
April 2021

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

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

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

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517040PMC
April 2021

Correction: Glaucoma in large-scale population-based epidemiology: a questionnaire-based proxy.

Eye (Lond) 2021 May;35(5):1527

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

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http://dx.doi.org/10.1038/s41433-021-01511-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182813PMC
May 2021

The Groningen electrocardiographic criteria for left ventricular hypertrophy: a sex-specific analysis.

Sci Rep 2021 03 23;11(1):6662. Epub 2021 Mar 23.

The Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.

The sensitivity of electrocardiogram (ECG) criteria to detect left ventricular hypertrophy (LVH) is low, especially in women. We determined sex-specific sensitivities of ECG-LVH criteria, and developed new criteria, using cardiovascular magnetic resonance imaging (CMR). Sensitivities of ECG-LVH criteria were determined in participants of the UK Biobank (N = 3632). LVH was defined when left ventricular mass was > 95% confidence interval (CI) according to age and sex. In a training cohort (75%, N = 2724), sex-specific ECG-LVH criteria were developed by investigating all possible sums of QRS-amplitudes in all 12 leads, and selecting the sum with the highest pseudo-R and area under the curve to detect LVH. Performance was assessed in a validation cohort (25%, N = 908), and association with blood pressure change was investigated in an independent cohort. Sensitivities of ECG-LVH criteria were low, especially in women. Newly developed Groningen-LVH criterion for women (Q + R + R + R + S + S + S + S) outperformed all ECG-LVH criteria with a sensitivity of 42% (95% CI 35-49%). In men, newly developed criterion ((R + R + S + S + S) × QRS duration) was equally sensitive as 12-lead sum with a sensitivity of 44% (95% CI 37-51%) and outperformed the other criteria. In an independent cohort, the Groningen-LVH criteria were strongest associated with change in systolic blood pressure. Our proposed CMR sex-specific Groningen-LVH criteria improve the sensitivity to detect LVH, especially in women. Further validation and its association with clinical outcomes is warranted.
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http://dx.doi.org/10.1038/s41598-021-83137-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988153PMC
March 2021

Effect of metabolic genetic variants on long-term disease comorbidity in patients with type 2 diabetes.

Sci Rep 2021 02 2;11(1):2794. Epub 2021 Feb 2.

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

Underlying genetic determinants contribute to developing type 2 diabetes (T2D) future diseases. The present study aimed to identify which genetic variants are associated with the incident of the major T2D co-morbid disease. First, we conducted a discovery study by investigating the genetic associations of comorbid diseases within the framework of the Utrecht Cardiovascular Pharmacogenetic studies by turning information of > 25 years follow-up data of 1237 subjects whom were genotyped and included in the discovery study. We performed Cox proportional-hazards regression to examine associations between genetic variants and comorbid diseases including cardiovascular diseases (CVD), chronic eye disease, cancer, neurologic diseases and chronic kidney disease. Secondly, we replicated our findings in two independent cohorts consisting of 1041 subjects. Finally, we performed a meta-analysis by combining the discovery and two replication cohorts. We ascertained 390 (39.7%) incident cases of CVD, 182 (16.2%) of chronic eye disease, 155 (13.8%) of cancer, 31 (2.7%) of neurologic disease and 13 (1.1%) of chronic kidney disease during a median follow-up of 10.2 years. In the discovery study, we identified a total of 39 Single Nucleotide Polymorphisms (SNPs) associated with comorbid diseases. The replication study, confirmed that rs1870849 and rs8051326 may play a role in the incidence of chronic eye disease in T2D patients. Half of patients developed at least one comorbid disease, with CVD occurring most often and earliest followed by chronic eye disease. Further research is needed to confirm the associations of two associated SNPs with chronic eye disease in T2D.
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http://dx.doi.org/10.1038/s41598-021-82276-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854581PMC
February 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

The relationship between dry eye and sleep quality.

Ocul Surf 2021 04 6;20:13-19. Epub 2021 Jan 6.

Departments of Ophthalmology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Postbus 30.001, Groningen, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Postbus 30.001, Groningen, the Netherlands; Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Hospital, Lambeth Palace Road, Waterloo, London, SE1 7EH, United Kingdom. Electronic address:

Purpose: Sleep is an important determinant of health and quality of life. This study aimed to clarify the association between dry eye and sleep quality using a large population-based cohort.

Methods: 71,761 participants (19-94 yrs, 59.4% female) from the Lifelines cohort in the Netherlands were assessed for dry eye using the Women's Health Study Dry Eye Questionnaire. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Logistic regression was used to examine the relationship between poor sleep quality (PSQI score >5) and dry eye, while correcting for age, sex, BMI, education, income, and 51 possible confounding comorbidities, including autoimmune diseases and psychiatric disorders.

Results: Overall, 8.9% of participants had dry eye. Of these, 36.4% had poor sleep quality compared to 24.8% of controls (OR 1.52 (95%CI 1.44-1.60), P < 0.0001, corrected for age and sex). After correcting for all comorbidities, dry eye was still associated with poor sleep (OR 1.20 (95%CI 1.11-1.28), P < 0.0001). This relationship was seen across all ages and sexes. Patients with dry eye scored worse on all subcomponents of the PSQI. Almost one-in-two (44.9%) persons with dry eye symptoms "often" or "constantly" had poor sleep quality. This proportion was similar to participants with sleep apnea and osteoarthritis. Additionally, increasing symptom frequency was tied to increased prevalence of poor sleep quality.

Conclusions: All components of sleep quality were significantly reduced in participants with dry eye, even after correcting for comorbidities. These results indicate the substantial impact of dry eye on patients' lives, especially for those with frequent symptoms.
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http://dx.doi.org/10.1016/j.jtos.2020.12.009DOI Listing
April 2021

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

Mol Psychiatry 2021 06 8;26(6):2148-2162. Epub 2021 Jan 8.

Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33520, Finland.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
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http://dx.doi.org/10.1038/s41380-020-00987-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263810PMC
June 2021

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

Bioinformatics 2021 Jan 8. Epub 2021 Jan 8.

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

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

Availability And Implementation: Our package is available at The Comprehensive R Archive Network (CRAN): https://CRAN.R-project.org/package=GWASinspector. Reference datasets and a detailed tutorial can be found at the package website at http://gwasinspector.com/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa1084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034536PMC
January 2021

Genetic pre-screening for glaucoma in population-based epidemiology: protocol for a double-blind prospective screening study within Lifelines (EyeLife).

BMC Ophthalmol 2021 Jan 7;21(1):18. Epub 2021 Jan 7.

Department of Ophthalmology, University of Groningen, University Medical Center Groningen, P.O.Box 30.001, 9700 RB, Groningen, Netherlands.

Background: Early detection of glaucoma is paramount to maintain patients' eyesight, however glaucomatous vision loss tends to begin in the periphery with up to 50% of patients unaware they are affected. Because glaucomatous vision loss is permanent, screening appears attractive, but currently is not cost-effective. Therefore we aim to investigate the utility of genetic pre-screening for glaucoma in a population-based setting, called EyeLife.

Methods: EyeLife adopts a double blind prospective design with contrasting groups. Selected participants (n = 1600) from the Lifelines cohort are 55 years of age or older, and of either the highest or lowest 20% of the genetic risk distribution for glaucoma. We obtained a highly curated list of genetic variants from the literature to obtain each participants' genetic risk for glaucoma. Participants will undergo comprehensive ophthalmic screening. The primary outcome is the relative risk of glaucoma given a high genetic risk compared to a low genetic risk.

Discussion: If genetic pre-screening is successful, it will increase the yield of a glaucoma screening program by focusing on high-risk individuals. This, in turn, may improve long-term visual health of middle-aged and elderly people.

Trial Registration: Ethics approval was obtained on January 31, 2019, and the study was retrospectively registered with the Netherlands Trial Register ( NL8718 ) on the 17th of June, 2020.
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http://dx.doi.org/10.1186/s12886-020-01771-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789075PMC
January 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021
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