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

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

SUBMITTER: Zheng Y

PROVIDER: S-EPMC7867117 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Zheng Yan Y Huang Tao T Wang Tiange T Mei Zhendong Z Sun Zhonghan Z Zhang Tao T Ellervik Christina C Chai Jin-Fang JF Sim Xueling X van Dam Rob M RM Tai E-Shyong ES Koh Woon-Puay WP Dorajoo Rajkumar R Saw Seang-Mei SM Sabanayagam Charumathi C Wong Tien Yin TY Gupta Preeti P Rossing Peter P Ahluwalia Tarunveer S TS Vinding Rebecca K RK Bisgaard Hans H Bønnelykke Klaus K Wang Yujie Y Graff Mariaelisa M Voortman Trudy T van Rooij Frank J A FJA Hofman Albert A van Heemst Diana D Noordam Raymond R Estampador Angela C AC Varga Tibor V TV Enzenbach Cornelia C Scholz Markus M Thiery Joachim J Burkhardt Ralph R Orho-Melander Marju M Schulz Christina-Alexandra CA Ericson Ulrika U Sonestedt Emily E Kubo Michiaki M Akiyama Masato M Zhou Ang A Kilpeläinen Tuomas O TO Hansen Torben T Kleber Marcus E ME Delgado Graciela G McCarthy Mark M Lemaitre Rozenn N RN Felix Janine F JF Jaddoe Vincent W V VWV Wu Ying Y Mohlke Karen L KL Lehtimäki Terho T Wang Carol A CA Pennell Craig E CE Schunkert Heribert H Kessler Thorsten T Zeng Lingyao L Willenborg Christina C Peters Annette A Lieb Wolfgang W Grote Veit V Rzehak Peter P Koletzko Berthold B Erdmann Jeanette J Munz Matthias M Wu Tangchun T He Meian M Yu Caizheng C Lecoeur Cécile C Froguel Philippe P Corella Dolores D Moreno Luis A LA Lai Chao-Qiang CQ Pitkänen Niina N Boreham Colin A CA Ridker Paul M PM Rosendaal Frits R FR de Mutsert Renée R Power Chris C Paternoster Lavinia L Sørensen Thorkild I A TIA Tjønneland Anne A Overvad Kim K Djousse Luc L Rivadeneira Fernando F Lee Nanette R NR Raitakari Olli T OT Kähönen Mika M Viikari Jorma J Langhendries Jean-Paul JP Escribano Joaquin J Verduci Elvira E Dedoussis George G König Inke I Balkau Beverley B Coltell Oscar O Dallongeville Jean J Meirhaeghe Aline A Amouyel Philippe P Gottrand Frédéric F Pahkala Katja K Niinikoski Harri H Hyppönen Elina E März Winfried W Mackey David A DA Gruszfeld Dariusz D Tucker Katherine L KL Fumeron Frédéric F Estruch Ramon R Ordovas Jose M JM Arnett Donna K DK Mook-Kanamori Dennis O DO Mozaffarian Dariush D Psaty Bruce M BM North Kari E KE Chasman Daniel I DI Qi Lu L

European journal of epidemiology 20200507 7

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide a ...[more]

PMID: 32383070

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Project description:Purpose: Birth weight has a profound long-term impact on individual's predisposition to various diseases at adulthood-a hypothesis commonly referred to as the fetal origins of adult diseases. However, it is not fully clear to what extent the fetal origins of adult diseases hypothesis holds and it is also not completely known what types of adult diseases are causally affected by birth weight. Materials and methods: Mendelian randomization using multiple genetic instruments associated with birth weight was performed to explore the causal relationship between birth weight and adult diseases. The causal relationship between birth weight and 21 adult diseases as well as 38 other complex traits was examined based on data collected from 37 large-scale genome-wide association studies with up to 340,000 individuals of European ancestry. Causal effects of birth weight were estimated using inverse-variance weighted methods. The identified causal relationships between birth weight and adult diseases were further validated through extensive sensitivity analyses, bias calculation, and simulations. Results: Among the 21 adult diseases, three were identified to be inversely causally affected by birth weight after the Bonferroni correction. The measurement unit of birth weight was defined as its standard deviation (i.e., 488 g), and one unit lower birth weight was causally related to an increased risk of coronary artery disease (CAD), myocardial infarction (MI), type 2 diabetes (T2D), and BMI-adjusted T2D, with the estimated odds ratios of 1.34 [95% confidence interval (CI) 1.17-1.53], 1.30 (95% CI 1.13-1.51), 1.41 (95% CI 1.15-1.73), and 1.54 (95% CI 1.25-1.89), respectively. All these identified causal associations were robust across various sensitivity analyses that guard against various confounding due to pleiotropy or maternal effects as well as reverse causation. In addition, analysis on 38 additional complex traits did not identify candidate traits that may mediate the causal association between birth weight and CAD/MI/T2D. Conclusions: The results suggest that lower birth weight is causally associated with an increased risk of CAD, MI, and T2D in later life, supporting the fetal origins of adult diseases hypothesis.

Project description:BackgroundPrevious observational studies have shown that there is an important relationship between gut microbiota and hypertension, we performed a two-sample Mendelian randomization analysis to examine whether the gut microbiota is causally related to hypertension in order to find a basis for potential diagnostic or intervention approaches for hypertension.MethodsWe obtained significant single nucleotide polymorphisms related to gut microbiota and hypertension from publicly available genome-wide association studies for a two-sample Mendelian randomization study. A total of 18,340 individual genome-wide genotype data were included from 24 population-based cohorts. The inverse-variance weighted meta-analysis is the main analytical method for evaluating causal relationships, and the Mendelian randomization research results have been validated through a series of sensitivity analyses.ResultsThe inverse-variance weighted analysis results indicated that phylum Verrucomicrobia (OR:0.831, 95%CI: 0.710-0.972; p = 0.021), family BacteroidalesS24.7group (OR:0.672, 95%CI: 0.496-0.911; p = 0.01), family Bifidobacteriaceae (OR:0.709, 95%CI:0.569-0.884, p = 0.002), genus Adlercreutzia (OR: 0.991, 95%CI: 0.982-0.999, p = 0.035), genus Phascolarctacterium (OR:0.819, 95%CI:0.685-0.981; p = 0.03), genus LachnospiraceaeNK4A136group (OR:0.990, 95%CI:0.981-0.999; p = 0.025), and genus Ruminococcus2 (OR:0.988, 95%CI: 0.979-0.997; p = 0.008) had protective causal effects on hypertension. The Family Alcaliginaceae (OR:1.011, 95%CI:1.000-1.021, p = 0.04), Genus Anaerostipes (OR:1.375, 95%CI:1.096-1.653; p = 0.025), Genus Collinsella (OR:1.899, 95%CI:1.361-2.348; p = 0.02), and Genus Lachnospiraceae_UCG_010 (OR:1.536, 95%CI:1.072-2.202; p = 0.019) were associated with a higher risk of HTN. The reverse Mendelian randomization analysis results showed no reverse causal relationship between HTN and these bacterial taxa.ConclusionOur Mendelian randomization analysis results indicate a potential causal relationship between these bacterial taxa and hypertension, providing a new perspective for the treatment and prevention of hypertension.

Project description:Background: The association between educational attainment (EA) and offspring birth weight (BW) has been reported by several traditional epidemiological studies. However, evidence for this association tends to be mixed and confounded. This study aimed to investigate the causal association between EA of parents and offspring BW. Methods: Here, we carried out a two-sample bidirectional Mendelian randomization (MR) analysis to examine the causal association between EA of males (n = 131,695) and females (n = 162,028) and offspring BW using genetic instruments. Summary statistics of EA associated single nucleotide polymorphisms (SNPs) were extracted from a GWAS incorporating 293,723 individuals of European descent performed by the Social Science Genetic Association Consortium (SSGAC), and the effects of these SNPs on offspring BW were estimated using a GWAS meta-analysis of 86,577 participants of European descent from 25 studies. Univariable MR analyses were conducted using the inverse-variance weighted (IVW) method and four other methods. Further sensitivity analyses were carried out to test the viability of the results. Multivariable MR was used to examine the confounders between the exposure and outcome. Results: The result shows evidence that the offspring BW is positively causally affected by female EA. Each one standard deviation (SD) increase in female EA was associated with 0.24 SD higher of offspring BW (95% confidence interval [CI], 0.10 to 0.37, p < 0.001 for the IVW method). Similarly, change in offspring BW was 0.21 SD (95% CI: 0.07 to 0.34, p = 2.82 × 10-3) per one SD higher in male EA. No causal effect of BW on EA was found by any of the five methods. The causal association between female EA and offspring BW maintained after adjusting for alcoholic drinks per week and BMI. The effect of male EA on offspring BW was attenuated when we adjusted for BMI and alcoholic drinks per week using multivariable MR analysis. Conclusion: Our study indicated that female EA is positively causally associated with offspring BW. The association between male EA and offspring BW may be confounded by alcoholic drinks per week and BMI.

Project description:ObjectiveThis study aimed to investigate the causal associations between several liver traits (liver iron content, percent liver fat, alanine transaminase levels, and liver volume) and colorectal cancer (CRC) risk using a Mendelian randomization (MR) approach to improve our understanding of the disease and its management.MethodsGenetic variants were used as instrumental variables, extracted from genome-wide association studies (GWAS) datasets of liver traits and CRC. The Two-Sample MR package in R was used to conduct inverse variance weighted (IVW), MR Egger, Maximum likelihood, Weighted median, and Inverse variance weighted (multiplicative random effects) MR approaches to generate overall estimates of the effect. MR analysis was conducted with Benjamini-Hochberg method-corrected P values to account for multiple testing (P < 0.013). MR-PRESSO was used to identify and remove outlier genetic variants in Mendelian randomization (MR) analysis. The MR Steiger test was used to assess the validity of the assumption that exposure causes outcomes. Leave-one-out validation, pleiotropy, and heterogeneity testing were also conducted to ensure the reliability of the results. Multivariable MR was utilized for validation of our findings using the IVW method while also adjusting for potential confounding or pleiotropy bias.ResultsThe MR analysis suggested a causal effect between liver volume and a reduced risk of CRC (OR 0.60; 95% CI, 0.44-0.82; P = 0.0010) but did not provide evidence for causal effects of liver iron content, percent liver fat, or liver alanine transaminase levels. The MR-PRESSO method did not identify any outliers, and the MR Steiger test confirmed that the causal direction of the analysis results was correct in the Mendelian randomization analysis. MR results were consistent with heterogeneity and pleiotropy analyses, and leave-one-out analysis demonstrated the overall values obtained were consistent with estimates obtained when all available SNPs were included in the analysis. Multivariable MR was utilized for validation of our findings using the IVW method while also adjusting for potential confounding or pleiotropy bias.ConclusionThe study provides tentative evidence for a causal role of liver volume in CRC, while genetically predicted levels of liver iron content, percent liver fat, and liver alanine transaminase levels were not associated with CRC risk. The findings may inform the development of targeted therapeutic interventions for colorectal liver metastasis (CRLM) patients, and the study highlights the importance of MR as a powerful epidemiological tool for investigating causal associations between exposures and outcomes.

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

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

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