Publications by authors named "Fernando Pires Hartwig"

37 Publications

Association between cesarean section and human capital in adulthood: 1982 and 1993 Pelotas birth cohorts, Rio Grande do Sul State, Brazil.

Cad Saude Publica 2021;37(9):e00235520. Epub 2021 Sep 24.

Universidade Federal de Pelotas, Pelotas, Brasil.

This study aims to assess the association between mode of delivery and human capital among young adults enrolled in the 1982 and 1993 Pelotas birth cohorts, Rio Grande do Sul State, Brasil. In 1982 and 1993, the maternity hospitals of the municipality were daily visited, the births identified, and those live births, whose family lived in the urban area of Pelotas, were examined and their mothers interviewed. Information on mode of delivery, vaginal or cesarean, was provided by the mother in the perinatal study. Performance in intelligence tests achieved schooling and income were evaluated in the 30 years visit at the 1982 cohort. At the 1993 cohort, schooling and income were assessed at the 22 years visit, whereas IQ was evaluated at 18 years. Tobacco smoking in adulthood and type of school was used as negative outcomes to strength causal inference. Initially, cesarean section was positively associated with human capital at adulthood, with the exception of income in the 1993 cohort. After controlling for confounders, the magnitude of the associations was strongly reduced, and the regression coefficients were close to the null value. The negative outcome analysis showed that, after controlling for confounding variables, the mode of delivery was not associated with tobacco smoking and type of school. Suggesting that the variables included in the regression model to control for confounding, provided an adequate adjustment and it is unlikely that the results are due to residual confounding by socioeconomic status. On the other hand, considering the short- and long-term risks and the epidemic of cesarean sections, measures should be implemented to reduce its prevalence.
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http://dx.doi.org/10.1590/0102-311X00235520DOI Listing
October 2021

Influenza vaccination in older adults during the COVID-19 pandemic: a population-based study in 133 Brazilian cities.

Cien Saude Colet 2021 Aug 11;26(8):2937-2947. Epub 2021 Jun 11.

Universidade Federal de Pelotas. Av. Marechal Deodoro 1160 3º piso, Centro. 96020-220 Pelotas RS Brasil.

Routine immunization during pandemics can be harmed. This study estimated the influenza vaccination coverage in older adults during the COVID-19 through the EPICOVID-19, a population-based study conducted in 133 cities from the 26 Brazilian states and Federal District. We selected 25 census tracts per city, with probability proportional to the tract's size, ten households by census tract, and one random individual interviewed. A total of 8,265 older adults (≥60 years old) were interviewed and asked whether they had been vaccinated against flu in 2020. Vaccination coverage was 82.3% (95% CI: 80.1-84.2) with no difference by gender, age, and region; higher vaccination coverage was observed among the wealthiest (84.7% versus 80.1% in the poorest) and among the more educated (87.3% versus 83.2% less educated); lower coverage among indigenous (56.9% versus > 80% among other ethnic groups). A positive association was identified with the number of comorbidities among men but not among women. Most of the population was vaccinated (97.5%) in the public health system. The private network was chosen mainly in the South by the wealthiest and more educated. Vaccination coverage was seven percentage points lower than the government target (90%), and inequalities should be reversed in future campaigns.
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http://dx.doi.org/10.1590/1413-81232021268.09382021DOI Listing
August 2021

Chronic non-communicable diseases and COVID-19: EPICOVID-19 Brazil results.

Rev Saude Publica 2021 2;55:38. Epub 2021 Jun 2.

Universidade Federal de Pelotas. Programa de Pós-Graduação em Epidemiologia. Pelotas, RS, Brasil.

Objective: Describing the prevalence of chronic diseases and associated socioeconomic and demographic factors, evaluating the patterns of social distancing and the antibodies prevalence against SARS-CoV-2 and COVID-19 symptoms in carriers and non-carriers of chronic diseases.

Methods: Data from 77,075 individuals aged 20 to 59 from three steps of the EPICOVID-19 Brazil (a nationwide serological survey conducted between May and June, 2021) were assessed. The presence of antibodies against SARS-CoV-2 was examined by rapid tests. Self-reported prevalence of hypertension, diabetes, asthma, cancer, chronic kidney disease and heart disease were investigated. The prevalence of mask use, adherence to isolation measures and antibodies were evaluated separately amid carriers and non-carriers of chronic diseases. The prevalence of symptoms was analyzed among carriers and non-carriers of chronic diseases with antibodies.

Results: The prevalence of at least one chronic disease was 43%, higher in the Southeast region, among white and indigenous individuals, women, less schooled and in lower socioeconomic position. The use of masks when leaving home was similar among carriers and non-carriers of chronic diseases (98%). The proportion of participants who reported adherence to isolation measures was higher amid carriers (15.9%) than non-carriers (24.9%) of chronic diseases. The prevalence of antibodies to SARS-CoV-2 was similar amongst carriers and non-carriers (2.4% and 2.3%). The prevalence of cough, dyspnea, palpitations and myalgia was significantly higher among carriers, but the proportion of symptomatic patients was similar between groups.

Conclusion: The prevalence of chronic diseases in Brazil is high and the COVID-19 pandemic affects carriers and non-carriers of chronic diseases similarly. Carriers present more severe forms of COVID-19 and higher prevalence of symptoms. Greater adherence to social distancing measures among chronic patients is disassociated from a lower incidence of COVID-19 in this group.
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http://dx.doi.org/10.11606/s1518-8787.2021055003673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139841PMC
June 2021

Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations.

Int J Epidemiol 2021 Feb 23. Epub 2021 Feb 23.

Medical Research Council Integrative Epidemiology Unit, at the University of Bristol, Bristol, UK.

Background: Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables.

Methods: We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR.

Results: In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index.

Conclusions: Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.
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http://dx.doi.org/10.1093/ije/dyaa266DOI Listing
February 2021

Influence of maternal pre-pregnancy nutritional status on offspring anthropometric measurements and body composition in three Brazilian Birth Cohorts.

Public Health Nutr 2021 04 2;24(5):882-894. Epub 2020 Dec 2.

Postgraduate Program in Epidemiology, Federal University of Pelotas, Marechal Deodoro, 1160 3° floor, Pelotas, Pelotas 96020-220, Brazil.

Objective: We aimed at evaluating the association of maternal pre-pregnancy nutritional status with offspring anthropometry and body composition. We also evaluated whether these associations were modified by gender, diet and physical activity and mediated by birth weight.

Design: Birth cohort study.

Setting: Waist circumference was measured with an inextensible tape, and fat and lean mass were measured using dual-energy X-ray absorptiometry. Multiple linear regression was used to adjust for possible confounders and allele score of BMI. We carried out mediation analysis using G-formula.

Participants: In 1982, 1993 and 2004, all maternity hospitals in Pelotas (South Brazil) were visited daily and all live births whose families lived in the urban area of the city were evaluated. These subjects have been followed up at different ages.

Results: Offspring of obese mothers had on average higher BMI, waist circumference and fat mass index than those of normal weight mothers, and these differences were higher among daughters. The magnitudes of the association were similar in the cohorts, except for height, where the association pattern was not clear. In the 1982 cohort, further adjustment for a BMI allele score had no material influence on the magnitude of the associations. Mediation analyses showed that birth weight captured part of this association.

Conclusions: Our findings suggest that maternal pre-pregnancy nutritional status is positively associated with offspring BMI and adiposity in offspring. And this association is higher among daughters whose mother was overweight or obese and, birth weight explains part of this association.
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http://dx.doi.org/10.1017/S1368980020004887DOI Listing
April 2021

Association between Breastfeeding and DNA Methylation over the Life Course: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC).

Nutrients 2020 Oct 29;12(11). Epub 2020 Oct 29.

MRC Integrative Epidemiology Unit, Population Health Science, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK.

Background: Breastfeeding is associated with short and long-term health benefits. Long-term effects might be mediated by epigenetic mechanisms, yet the literature on this topic is scarce. We performed the first epigenome-wide association study of infant feeding, comparing breastfed vs non-breastfed children. We measured DNA methylation in children from peripheral blood collected in childhood (age 7 years, N = 640) and adolescence (age 15-17 years, N = 709) within the Accessible Resource for Integrated Epigenomic Studies (ARIES) project, part of the larger Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Cord blood methylation (N = 702) was used as a negative control for potential pre-natal residual confounding.

Results: Two differentially-methylated sites presented directionally-consistent associations with breastfeeding at ages 7 and 15-17 years, but not at birth. Twelve differentially-methylated regions in relation to breastfeeding were identified, and for three of them there was evidence of directional concordance between ages 7 and 15-17 years, but not between birth and age 7 years.

Conclusions: Our findings indicate that DNA methylation in childhood and adolescence may be predicted by breastfeeding, but further studies with sufficiently large samples for replication are required to identify robust associations.
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http://dx.doi.org/10.3390/nu12113309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692466PMC
October 2020

EPICOVID19 protocol: repeated serological surveys on SARS-CoV-2 antibodies in Brazil.

Cien Saude Colet 2020 Sep 28;25(9):3573-3578. Epub 2020 Aug 28.

Universidade Federal de Pelotas, Pelotas, RS, Brazil,

The first case of COVID-19 was reported in China in December 2019, and, as the virus has spread worldwide, the World Health Organization declared it a pandemic. Estimates on the number of COVID-19 cases do not reflect it real magnitude as testing is limited. Population based data on the proportion of the population with antibodies is relevant for planning public health policies. We aim to assess the prevalence of SARS-CoV-2 antibodies, presence of signs and symptoms of COVID-19, and adherence to isolation measures. A random sample comprising 133 sentinel cities from all states of the country will be selected. Three serological surveys, three weeks apart, will be conducted. The most populous municipality in each intermediate region of the country, defined by the Brazilian Institute of Geography and Statistics, was chosen as sentinel city. In each city, 25 census tracts will be selected, and 10 households will be systematically sampled in each tract, totaling 33,250 participants. In each household, one inhabitant will be randomly selected to be interviewed and tested for antibodies against SARS-CoV-2, using WONDFO SARS-CoV-2 Antibody Test. By evaluating a representative sample of Brazilian sentinel sites, this study will provide essential information for the design of health policies.
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http://dx.doi.org/10.1590/1413-81232020259.25532020DOI Listing
September 2020

EPICOVID19 protocol: repeated serological surveys on SARS-CoV-2 antibodies in Brazil.

Cien Saude Colet 2020 Sep 28;25(9):3573-3578. Epub 2020 Aug 28.

Universidade Federal de Pelotas, Pelotas, RS, Brazil,

The first case of COVID-19 was reported in China in December 2019, and, as the virus has spread worldwide, the World Health Organization declared it a pandemic. Estimates on the number of COVID-19 cases do not reflect it real magnitude as testing is limited. Population based data on the proportion of the population with antibodies is relevant for planning public health policies. We aim to assess the prevalence of SARS-CoV-2 antibodies, presence of signs and symptoms of COVID-19, and adherence to isolation measures. A random sample comprising 133 sentinel cities from all states of the country will be selected. Three serological surveys, three weeks apart, will be conducted. The most populous municipality in each intermediate region of the country, defined by the Brazilian Institute of Geography and Statistics, was chosen as sentinel city. In each city, 25 census tracts will be selected, and 10 households will be systematically sampled in each tract, totaling 33,250 participants. In each household, one inhabitant will be randomly selected to be interviewed and tested for antibodies against SARS-CoV-2, using WONDFO SARS-CoV-2 Antibody Test. By evaluating a representative sample of Brazilian sentinel sites, this study will provide essential information for the design of health policies.
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http://dx.doi.org/10.1590/1413-81232020259.25532020DOI Listing
September 2020

Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses.

Nat Commun 2020 07 14;11(1):3519. Epub 2020 Jul 14.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, BS8 2BN, Bristol, UK.

Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.
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http://dx.doi.org/10.1038/s41467-020-17117-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360778PMC
July 2020

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

BMC Cardiovasc Disord 2019 10 29;19(1):240. Epub 2019 Oct 29.

Department Primary Care & Population Health, University College London, London, UK.

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.

Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.

Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.

Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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http://dx.doi.org/10.1186/s12872-019-1187-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820948PMC
October 2019

Assessing causality in the association between attention-deficit/hyperactivity disorder and obesity: a Mendelian randomization study.

Int J Obes (Lond) 2019 12 18;43(12):2500-2508. Epub 2019 Apr 18.

Postgraduate Program in Epidemiology, Universidade Federal de Pelotas, Pelotas, Brazil.

Background/objectives: Attention-deficit hyperactivity disorder (ADHD), one of the most common neurodevelopmental disorders in childhood and adolescence, is associated with obesity in observational studies. However, it is unclear whether ADHD contributes to, results from or is merely correlated with obesity. This study evaluates the presence and direction of a causal effect between ADHD and obesity.

Subjects/methods: We performed a bidirectional two-sample Mendelian randomization using summary data from consortia of genome-wide association studies to investigate if ADHD (N = 55,374) has a causal effect on body mass index (BMI) in childhood (N = 35,668) and adulthood (N = 322,154-500,000), and vice-versa. The main analysis was performed using the inverse variance weighted (IVW) method. As sensitivity analyses, we used other Mendelian randomization methods that are more robust to horizontal pleiotropy (i.e., MR-Egger, weighted mode, and penalized weighted median estimators), as well as stratified the analysis by the putative mechanisms of genetic instruments (i.e., pathways involved or not in neurological processes).

Results: The IVW method indicated a positive causal effect of BMI on ADHD: β = 0.324 (95% CI 0.198 to 0.449, p < 0.001; expressed as change in ln(odds ratio) of ADHD per each additional SD unit of BMI). IVW estimates were directionally consistent with other methods. On the other hand, we did not find consistent evidence for a causal effect of ADHD genetic liability on BMI.

Conclusions: The results suggested that higher BMI increases the risk of developing ADHD, but not the other way around.
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http://dx.doi.org/10.1038/s41366-019-0346-8DOI Listing
December 2019

Efficacy of Regular Exercise During Pregnancy on the Prevention of Postpartum Depression: The PAMELA Randomized Clinical Trial.

JAMA Netw Open 2019 01 4;2(1):e186861. Epub 2019 Jan 4.

Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil.

Importance: Interventions to reduce postpartum depression have mainly focused on enhancing screening to increase treatment rates among women. Preventive approaches are timely from a population health perspective, particularly in low- and middle-income countries where access to mental health services is limited.

Objective: To assess the efficacy of regular exercise during pregnancy on the prevention of postpartum depression.

Design, Setting, And Participants: This randomized clinical trial examines a prespecified secondary outcome of the Physical Activity for Mothers Enrolled in Longitudinal Analysis (PAMELA) Study, a parallel-group, randomized clinical trial. This trial was nested in the 2015 Pelotas (Brazil) Birth Cohort Study. Between August 27, 2014, and March 14, 2016, pregnant women between 16 and 20 weeks of gestation with no contraindications to exercise were randomized 1:2 to the intervention group or control group via computer-generated randomization using a block size of 9. Data were analyzed from March 7 to May 2, 2018.

Interventions: Participants assigned to the intervention were engaged in a 16-week supervised exercise program including aerobic and resistance training delivered in 60-minute sessions 3 times per week.

Main Outcomes And Measures: Postpartum depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale 3 months after birth. A score of 12 or greater was defined as screening positive for postpartum depression. Primary analysis was performed on a complete case basis (90% of participants who had the primary end point ascertained).

Results: A total of 639 participants (mean [SD] age, 27.1 [5.1] years; mean gestational age, 16.5 [1.5] weeks) were randomly assigned to the intervention group (n = 213) or control group (n = 426). Compliance with the protocol, defined as having engaged in at least 70% of exercise sessions, was low (40.4%). There was no significant difference in mean (SD) scores for postpartum depression between the intervention group (4.8 [3.7]) and the control group (5.4 [4.1]) (mean difference, -0.6; 95% CI, -1.3 to 0.1). There was also no significant difference in rates of postpartum depression between the intervention group (12 of 192 [6.3%]) and the control group (36 of 387 [9.3%]) (odds ratio, 0.65; 95% CI, 0.33-1.28). Instrumental variable analysis indicated that noncompliance may have attenuated the effect estimates obtained in the primary analysis.

Conclusions And Relevance: Moderate-intensity exercise during pregnancy did not lead to significant reductions in postpartum depression. However, noncompliance to the intervention protocol was substantial and may have led to underestimations of the possible benefits of exercise. The point estimates for this study are in the same direction as the previous randomized clinical trial on this topic. Future studies on how to promote regular exercise during pregnancy to improve compliance, particularly targeting young and less educated women, are warranted before further trials are undertaken.

Trial Registration: ClinicalTrials.gov Identifier: NCT02148965.
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http://dx.doi.org/10.1001/jamanetworkopen.2018.6861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324311PMC
January 2019

Effect modification of FADS2 polymorphisms on the association between breastfeeding and intelligence: results from a collaborative meta-analysis.

Int J Epidemiol 2019 02;48(1):45-57

Population Health Sciences, University of Bristol, Bristol, UK.

Background: Accumulating evidence suggests that breastfeeding benefits children's intelligence, possibly due to long-chain polyunsaturated fatty acids (LC-PUFAs) present in breast milk. Under a nutritional adequacy hypothesis, an interaction between breastfeeding and genetic variants associated with endogenous LC-PUFAs synthesis might be expected. However, the literature on this topic is controversial.

Methods: We investigated this gene × environment interaction through a collaborative effort. The primary analysis involved >12 000 individuals and used ever breastfeeding, FADS2 polymorphisms rs174575 and rs1535 coded assuming a recessive effect of the G allele, and intelligence quotient (IQ) in Z scores.

Results: There was no strong evidence of interaction, with pooled covariate-adjusted interaction coefficients (i.e. difference between genetic groups of the difference in IQ Z scores comparing ever with never breastfed individuals) of 0.12[(95% confidence interval (CI): -0.19; 0.43] and 0.06 (95% CI: -0.16; 0.27) for the rs174575 and rs1535 variants, respectively. Secondary analyses corroborated these results. In studies with ≥5.85 and <5.85 months of breastfeeding duration, pooled estimates for the rs174575 variant were 0.50 (95% CI: -0.06; 1.06) and 0.14 (95% CI: -0.10; 0.38), respectively, and 0.27 (95% CI: -0.28; 0.82) and -0.01 (95% CI: -0.19; 0.16) for the rs1535 variant.

Conclusions: Our findings did not support an interaction between ever breastfeeding and FADS2 polymorphisms. However, subgroup analysis suggested that breastfeeding may supply LC-PUFAs requirements for cognitive development if breastfeeding lasts for some (currently unknown) time. Future studies in large individual-level datasets would allow properly powered subgroup analyses and further improve our understanding on the breastfeeding × FADS2 interaction.
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http://dx.doi.org/10.1093/ije/dyy273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380307PMC
February 2019

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.

Nat Commun 2018 07 30;9(1):2976. Epub 2018 Jul 30.

University of California Los Angeles, Los Angeles, CA, 90095, USA.

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
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http://dx.doi.org/10.1038/s41467-018-05369-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065313PMC
July 2018

Bias in Mendelian randomization due to assortative mating.

Genet Epidemiol 2018 10 3;42(7):608-620. Epub 2018 Jul 3.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Mendelian randomization (MR) has been increasingly used to strengthen causal inference in observational epidemiology. Methodological developments in the field allow detecting and/or adjusting for different potential sources of bias, mainly bias due to horizontal pleiotropy (or "off-target" genetic effects). Another potential source of bias is nonrandom matching between spouses (i.e., assortative mating). In this study, we performed simulations to investigate the bias caused in MR by assortative mating. We found that bias can arise due to either cross-trait assortative mating (i.e., assortment on two phenotypes, such as highly educated women selecting taller men) or single-trait assortative mating (i.e., assortment on a single phenotype), even if the exposure and outcome phenotypes are not the phenotypes under assortment. The simulations also indicate that bias due to assortative mating accumulates over generations and that MR methods robust to horizontal pleiotropy are also affected by this bias. Finally, we show that genetic data from mother-father-offspring trios can be used to detect and correct for this bias.
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http://dx.doi.org/10.1002/gepi.22138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221130PMC
October 2018

Letter by Hartwig et al Regarding Article, "Evaluation of the Pleiotropic Effects of Statins: A Reanalysis of the Randomized Trial Evidence Using Egger Regression".

Arterioscler Thromb Vasc Biol 2018 05;38(5):e85-e86

Medical Research Council Integrative Epidemiology Unit, University of Bristol, United Kingdom.

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http://dx.doi.org/10.1161/ATVBAHA.118.310897DOI Listing
May 2018

Mendelian Randomization Concerns-Reply.

JAMA Psychiatry 2018 04 7;75(4):407-408. Epub 2018 Mar 7.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, England.

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http://dx.doi.org/10.1001/jamapsychiatry.2017.4725DOI Listing
April 2018

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

Am J Hum Genet 2018 03 15;102(3):375-400. Epub 2018 Feb 15.

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

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
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http://dx.doi.org/10.1016/j.ajhg.2018.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985266PMC
March 2018

Lactase Persistence and Body Mass Index: The Contribution of Mendelian Randomization.

Clin Chem 2018 01 29;64(1):4-6. Epub 2017 Nov 29.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK;

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http://dx.doi.org/10.1373/clinchem.2017.282673DOI Listing
January 2018

Inflammatory Biomarkers and Risk of Schizophrenia: A 2-Sample Mendelian Randomization Study.

JAMA Psychiatry 2017 12;74(12):1226-1233

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, England.

Importance: Positive associations between inflammatory biomarkers and risk of psychiatric disorders, including schizophrenia, have been reported in observational studies. However, conventional observational studies are prone to bias, such as reverse causation and residual confounding, thus limiting our understanding of the effect (if any) of inflammatory biomarkers on schizophrenia risk.

Objective: To evaluate whether inflammatory biomarkers have an effect on the risk of developing schizophrenia.

Design, Setting, And Participants: Two-sample mendelian randomization study using genetic variants associated with inflammatory biomarkers as instrumental variables to improve inference. Summary association results from large consortia of candidate gene or genome-wide association studies, including several epidemiologic studies with different designs, were used. Gene-inflammatory biomarker associations were estimated in pooled samples ranging from 1645 to more than 80 000 individuals, while gene-schizophrenia associations were estimated in more than 30 000 cases and more than 45 000 ancestry-matched controls. In most studies included in the consortia, participants were of European ancestry, and the prevalence of men was approximately 50%. All studies were conducted in adults, with a wide age range (18 to 80 years).

Exposures: Genetically elevated circulating levels of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-6 receptor (sIL-6R).

Main Outcomes And Measures: Risk of developing schizophrenia. Individuals with schizophrenia or schizoaffective disorders were included as cases. Given that many studies contributed to the analyses, different diagnostic procedures were used.

Results: The pooled odds ratio estimate using 18 CRP genetic instruments was 0.90 (random effects 95% CI, 0.84-0.97; P = .005) per 2-fold increment in CRP levels; consistent results were obtained using different mendelian randomization methods and a more conservative set of instruments. The odds ratio for sIL-6R was 1.06 (95% CI, 1.01-1.12; P = .02) per 2-fold increment. Estimates for IL-1Ra were inconsistent among instruments, and pooled estimates were imprecise and centered on the null.

Conclusions And Relevance: Under mendelian randomization assumptions, our findings suggest a protective effect of CRP and a risk-increasing effect of sIL-6R (potentially mediated at least in part by CRP) on schizophrenia risk. It is possible that such effects are a result of increased susceptibility to early life infection.
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http://dx.doi.org/10.1001/jamapsychiatry.2017.3191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583386PMC
December 2017

Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption.

Int J Epidemiol 2017 12;46(6):1985-1998

MRC Integrative Epidemiology Unit.

Background: Mendelian randomization (MR) is being increasingly used to strengthen causal inference in observational studies. Availability of summary data of genetic associations for a variety of phenotypes from large genome-wide association studies (GWAS) allows straightforward application of MR using summary data methods, typically in a two-sample design. In addition to the conventional inverse variance weighting (IVW) method, recently developed summary data MR methods, such as the MR-Egger and weighted median approaches, allow a relaxation of the instrumental variable assumptions.

Methods: Here, a new method - the mode-based estimate (MBE) - is proposed to obtain a single causal effect estimate from multiple genetic instruments. The MBE is consistent when the largest number of similar (identical in infinite samples) individual-instrument causal effect estimates comes from valid instruments, even if the majority of instruments are invalid. We evaluate the performance of the method in simulations designed to mimic the two-sample summary data setting, and demonstrate its use by investigating the causal effect of plasma lipid fractions and urate levels on coronary heart disease risk.

Results: The MBE presented less bias and lower type-I error rates than other methods under the null in many situations. Its power to detect a causal effect was smaller compared with the IVW and weighted median methods, but was larger than that of MR-Egger regression, with sample size requirements typically smaller than those available from GWAS consortia.

Conclusions: The MBE relaxes the instrumental variable assumptions, and should be used in combination with other approaches in sensitivity analyses.
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http://dx.doi.org/10.1093/ije/dyx102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837715PMC
December 2017

Education and coronary heart disease: mendelian randomisation study.

BMJ 2017 Aug 30;358:j3542. Epub 2017 Aug 30.

Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

 To determine whether educational attainment is a causal risk factor in the development of coronary heart disease. Mendelian randomisation study, using genetic data as proxies for education to minimise confounding. The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries. Findings from mendelian randomisation analyses were then compared against results from traditional observational studies (164 170 participants). Finally, genetic data from six additional consortia were analysed to investigate whether longer education can causally alter the common cardiovascular risk factors. The main analysis was of 543 733 men and women (from CARDIoGRAMplusC4D and SSGAC), predominantly of European origin. A one standard deviation increase in the genetic predisposition towards higher education (3.6 years of additional schooling), measured by 162 genetic variants that have been previously associated with education. Combined fatal and non-fatal coronary heart disease (63 746 events in CARDIoGRAMplusC4D). Genetic predisposition towards 3.6 years of additional education was associated with a one third lower risk of coronary heart disease (odds ratio 0.67, 95% confidence interval 0.59 to 0.77; P=3×10). This was comparable to findings from traditional observational studies (prevalence odds ratio 0.73, 0.68 to 0.78; incidence odds ratio 0.80, 0.76 to 0.83). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely, although this remains an untestable possibility. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favourable blood lipid profile. This mendelian randomisation study found support for the hypothesis that low education is a causal risk factor in the development of coronary heart disease. Potential mechanisms could include smoking, body mass index, and blood lipids. In conjunction with the results from studies with other designs, these findings suggest that increasing education may result in substantial health benefits.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594424PMC
http://dx.doi.org/10.1136/bmj.j3542DOI Listing
August 2017

Breastfeeding effects on DNA methylation in the offspring: A systematic literature review.

PLoS One 2017 3;12(3):e0173070. Epub 2017 Mar 3.

MRC Integrative Epidemiology Unit, School of Social & Community Medicine, University of Bristol, Bristol, United Kingdom.

Background: Breastfeeding benefits both infants and mothers. Recent research shows long-term health and human capital benefits among individuals who were breastfed. Epigenetic mechanisms have been suggested as potential mediators of the effects of early-life exposures on later health outcomes. We reviewed the literature on the potential effects of breastfeeding on DNA methylation.

Methods: Studies reporting original results and evaluating DNA methylation differences according to breastfeeding/breast milk groups (e.g., ever vs. never comparisons, different categories of breastfeeding duration, etc) were eligible. Six databases were searched simultaneously using Ovid, and the resulting studies were evaluated independently by two reviewers.

Results: Seven eligible studies were identified. Five were conducted in humans. Studies were heterogeneous regarding sample selection, age, target methylation regions, methylation measurement and breastfeeding categorisation. Collectively, the studies suggest that breastfeeding might be negatively associated with promoter methylation of LEP (which encodes an anorexigenic hormone), CDKN2A (involved in tumour suppression) and Slc2a4 genes (which encodes an insulin-related glucose transporter) and positively with promoter methylation of the Nyp (which encodes an orexigenic neuropeptide) gene, as well as influence global methylation patterns and modulate epigenetic effects of some genetic variants.

Conclusions: The findings from our systematic review are far from conclusive due to the small number of studies and their inherent limitations. Further studies are required to understand the actual potential role of epigenetics in the associations of breastfeeding with later health outcomes. Suggestions for future investigations, focusing on epigenome-wide association studies, are provided.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173070PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336253PMC
August 2017

Suggestive association between variants in IL1RAPL and asthma symptoms in Latin American children.

Eur J Hum Genet 2017 04 25;25(4):439-445. Epub 2017 Jan 25.

Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, Brazil.

Several genome-wide association studies have been conducted to investigate the influence of genetic polymorphisms in the development of allergic diseases, but few of them have included the X chromosome. The aim of present study was to perform an X chromosome-wide association study (X-WAS) for asthma symptoms. The study included 1307 children of which 294 were asthma cases. DNA was genotyped using 2.5 HumanOmni Beadchip from Illumina. Statistical analyses were performed in PLINK 1.9, MACH 1.0 and Minimac2. The variant rs12007907 (g.29483892C>A) in IL1RAPL gene was suggestively associated with asthma symptoms in discovery set (odds ratio (OR)=0.49, 95% confidence interval (CI): 0.37-0.67; P=3.33 × 10). This result was replicated in the ProAr cohort in men only (OR=0.45, 95% CI: 0.21-0.95; P=0.038). Furthermore, investigating the functional role of the rs12007907 on the production a Th2-type cytokine, IL-13, we found a negative association between the minor allele A with IL-13 production in the discovery set (P=0.044). Gene-based analysis revealed that NUDT10 was the most consistently associated with asthma symptoms in discovery sample. In conclusion, the rs12007907 variant in IL1RAPL gene was negatively associated with asthma and IL-13 production in our study and a sex-specific association was observed in one of the validation samples. It suggests an effect on asthma susceptibility and may explain differences in severe asthma frequency between women and men.
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http://dx.doi.org/10.1038/ejhg.2016.197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386417PMC
April 2017

PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study.

Lancet Diabetes Endocrinol 2017 02 29;5(2):97-105. Epub 2016 Nov 29.

Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

Background: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.

Methods: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.

Findings: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m, -0·09 to 0·30).

Interpretation: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.

Funding: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
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http://dx.doi.org/10.1016/S2213-8587(16)30396-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266795PMC
February 2017

Why internal weights should be avoided (not only) in MR-Egger regression.

Int J Epidemiol 2016 10 20;45(5):1676-1678. Epub 2016 Sep 20.

Medical Research Council Integrative Epidemiology Unit and.

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http://dx.doi.org/10.1093/ije/dyw240DOI Listing
October 2016

Body mass index and psychiatric disorders: a Mendelian randomization study.

Sci Rep 2016 09 7;6:32730. Epub 2016 Sep 7.

Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil.

Obesity is a highly prevalent risk factor for cardiometabolic diseases. Observational studies suggest that obesity is associated with psychiatric traits, but causal inference from such studies has several limitations. We used two-sample Mendelian randomization methods (inverse variance weighting, weighted median and MR-Egger regression) to evaluate the association of body mass index (BMI) with three psychiatric traits using data from the Genetic Investigation of Anthropometric Traits and Psychiatric Genomics consortia. Causal odds ratio estimates per 1-standard deviation increment in BMI ranged from 0.88 (95% CI: 0.62; 1.25) to 1.23 (95% CI: 0.65; 2.31) for bipolar disorder; 0.93 (0.78; 1.11) to 1.41 (0.87; 2.27) for schizophrenia; and 1.15 (95% CI: 0.92; 1.44) to 1.40 (95% CI: 1.03; 1.90) for major depressive disorder. Analyses removing potentially influential SNPs suggested that the effect estimates for depression might be underestimated. Our findings do not support the notion that higher BMI increases risk of bipolar disorder and schizophrenia. Although the point estimates for depression were consistent in all sensitivity analyses, the overall statistical evidence was weak. However, the fact that SNP-depression associations were estimated in relatively small samples reduced power to detect causal effects. This should be re-addressed when SNP-depression associations from larger studies become available.
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http://dx.doi.org/10.1038/srep32730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013405PMC
September 2016

Genomic ancestry and the social pathways leading to major depression in adulthood: the mediating effect of socioeconomic position and discrimination.

BMC Psychiatry 2016 09 5;16(1):308. Epub 2016 Sep 5.

Postgraduate Program in Epidemiology, Federal University of Pelotas, Rua Marechal Deodoro, 1160 - 3° Piso, Bairro Centro. Cep: 96020-220, Caixa Postal 464, Pelotas, RS, Brazil.

Background: Evidence suggests that there is an association between ethnicity/skin color and depression; however, many contextual and individual variables, like sense of discrimination and socioeconomic position (SEP), might influence the direction of this association. We assessed the association between African ancestry and major depression among young adults that have been followed-up since birth in a Southern Brazilian city, and the mediating effect of SEP and discrimination.

Methods: In 1982, all hospital deliveries in Pelotas (Southern Brazil) were identified; liveborns were examined and their mothers interviewed (n = 5914). In 2012-13, at 30 years of age, we used the Mini International Neuropsychiatric Interview (MINI) for major depression diagnosis. In addition, DNA samples were genotyped for approximately 2.5 million single nucleotide polymorphisms (SNPs) using Illumina (CA, USA) HumanOmni2.5-8v1 array. Genomic ancestry estimation was based on approximately 370 000 single nucleotide polymorphisms (SNPs) mutually available for the Pelotas cohort and selected samples (used as reference panels) of the HapMap and Human Genome Diversity (HGDP). We estimated prevalence ratios (PR) using Poisson regression models and evaluated the association between percentage of African ancestry and major depression. We used G-computation for mediation analysis.

Results: At 30 years, 3576 individuals were evaluated for major depression (prevalence = 7.9 %). Only individuals in the highest SEP, who had a percentage of African ancestry between >5-30 % and >30 % had a prevalence of major depression 2.16 (PR = 2.16 95 % CI [1.05-4.45]) and 2.74 (PR = 2.74 95 % CI [1.06-7.06]) times higher, than those with 5 % or less, respectively. Among these subjects, sense of discrimination by skin color, captured 84 % of the association between African ancestry and major depression.

Conclusion: SEP is an important effect modifier of the positive association between African ancestry and major depression. In addition, this association is predominantly mediated by the sense of feeling discriminated by skin color.
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http://dx.doi.org/10.1186/s12888-016-1015-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011949PMC
September 2016
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