Genome-wide meta-analysis identifies novel maternal risk variants and enables polygenic prediction of preeclampsia and gestational hypertension

Honigberg, Michael C.; Truong, Buu; Khan, Rehan; Xiao, Brenda; Bhatta, Laxmi; Vy, Ha My T.; Guerrero, Rafael F.; Schuermans, Art; Selvaraj, Margaret Sunitha; Patel, Aniruddh P.; Koyama, Satoshi; Cho, So Mi Jemma; Vellarikkal, Shamsudheen Karuthedath; Trinder, Mark; Urbut, Sarah; Gray, Kathryn J.; Brumpton, Ben; Patil, Snehal; Zöllner, Sebastian; Antopia, Mariah C.; Saxena, Richa; Nadkarni, Girish N.; Do, Ron; Yan, Qi; Pe’er, Itsik; Verma, Shefali S.; Gupta, Rajat M.; Haas, David M.; Martin, Hilary C.; Heel, David A. van; Laisk, Triin; Natarajan, Pradeep

doi:10.1101/2022.11.30.22282929

Cited by 4 publications

(11 citation statements)

References 107 publications

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“…A recently conducted phenome-wide association study investigated the relation between polygenic risk scores for pre-eclampsia/eclampsia and gestational hypertension with >1,000 phenotypes in men and also reported hypertension to be one of the key associated characteristics. 19 This is indicative that earlier hypertension is a main driver of the underlying mechanisms leading to a higher CVD risk in males. We also analysed the genetic liability to HDPs and CVD in nulligravidae.…”

Section: Hdps In Men and Nulligravidaementioning

confidence: 98%

“…Genetic correlation between HDPs and blood pressure has previously been demonstrated. 19 Notably, the genetic correlation between gestational hypertension and SBP was even higher than between SBP and DBP. 19 A previous MR analysis showed that higher genetically predicted SBP was also related to an elevated risk for pre-eclampsia/eclampsia.…”

Section: Hdps and Blood Pressurementioning

confidence: 99%

“…19 Notably, the genetic correlation between gestational hypertension and SBP was even higher than between SBP and DBP. 19 A previous MR analysis showed that higher genetically predicted SBP was also related to an elevated risk for pre-eclampsia/eclampsia. 25 Moreover, higher levels of genetically proxied blood pressure have been related to an increased risk of CVD in both women and men.…”

Section: Hdps and Blood Pressurementioning

confidence: 99%

“…For our instrumental variables, we used SNPs for pre-eclampsia/eclampsia and gestational hypertension identified by a recent genome-wide association study (GWAS) by Honigberg et al 19 We used effect sizes and standard errors from the discovery analysis, which excluded data from the UK Biobank, allowing two-sample MR. 19 As illustrated in Figure S1, twelve SNPs for pre-eclampsia/eclampsia and seven SNPs for gestational hypertension were identified by the GWAS. 19 We harmonised the summary-level data to be represented on the same strand. Furthermore, we excluded palindromic SNPs with allele frequencies between 0.45 and 0.55.…”

Section: Instrumental Variablementioning

confidence: 99%

“…24 The same is the case for 24 Moreover, a phenome-wide association analysis showed strong associations between polygenic risk scores of HDPs with CVD risk factors (such as hypertension, diabetes mellitus, hyperlipidaemia, and obesity) and CVD events (including ischaemic heart disease and coronary atherosclerosis) in women and men. 19 In addition, a recent MR analysis, which only included women for genetic associations with HDPs, showed genetically proxied HDPs to be related to a higher risk of coronary artery disease or ischaemic stroke. 11 Furthermore, genetically proxied pre-eclampsia and gestational hypertension were associated with a higher risk of coronary artery disease but not with risk of ischaemic stroke.…”

Section: Findings From Previous Studiesmentioning

confidence: 99%

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Hypertensive disorders of pregnancy and risk of cardiovascular disease: A Mendelian Randomisation study in the UK Biobank

Tschiderer

Schouw

Burgess

et al. 2023

Preprint

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Background:Observational studies show that hypertensive disorders of pregnancy (HDPs) are related to unfavourable maternal cardiovascular disease (CVD) risk profiles later in life. We investigated whether genetic liability to pre-eclampsia/eclampsia and gestational hypertension is associated with CVD risk factors and occurrence of CVD events. Methods:We obtained genetic associations with HDPs from a genome-wide association study and used individual-participant-data of women and men from the UK Biobank to obtain genetic associations with CVD risk factors and CVD events (defined as myocardial infarction or stroke). The rationale for including men and nulligravidae was to study genetic liability to HDPs and CVD risk without experiencing the underlying phenotype. We applied Mendelian Randomisation analysis using inverse variance weighted regression in our primary analysis. Results:We included 264,160 women (mean age 56.4 [SD 8.0]) and 223,043 men (mean age 56.7 [8.2]) with available genetic data. Genetically proxied pre-eclampsia/eclampsia was related to higher risk of CVD with odds ratios of 1.20 (1.01, 1.43) and 1.29 (1.08, 1.53) in women and men, respectively. For genetically proxied gestational hypertension, odds ratios for CVD were 1.22 (1.10, 1.36) and 1.28 (1.16, 1.42) in women and men, respectively. Furthermore, genetically proxied HDPs were associated with higher levels of systolic and diastolic blood pressure and younger age at hypertension diagnosis in both women and men. Conclusions:Genetic liability to HDPs including pre-eclampsia/eclampsia and gestational hypertension is associated with higher CVD risk, implying biological mechanisms relating to these disorders are causally related to CVD risk in both women and men.

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Section: Hdps In Men and Nulligravidaementioning

confidence: 98%

Section: Hdps and Blood Pressurementioning

confidence: 99%

Section: Hdps and Blood Pressurementioning

confidence: 99%

Section: Instrumental Variablementioning

confidence: 99%

Section: Findings From Previous Studiesmentioning

confidence: 99%

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Hypertensive disorders of pregnancy and risk of cardiovascular disease: A Mendelian Randomisation study in the UK Biobank

Tschiderer

Schouw

Burgess

et al. 2023

Preprint

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Adverse pregnancy outcomes and future risk of heart failure

Pabón

Misra

Honigberg

2023

Current Opinion in Cardiology

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Purpose of reviewCardiovascular disease (CVD) is the leading cause of death in women. Women with history of adverse pregnancy outcomes (APOs) have approximately two-fold risk of future CVD, but until recently the association with future heart failure (HF) was unclear. Here, we summarize evidence for associations of APOs with HF, potential underlying mechanisms, and future directions for clinical translation.Recent findingsWomen with history of hypertensive disorders of pregnancy (HDPs) have roughly two-fold risk of future HF compared with other parous women even after accounting for interval development of coronary artery disease. The HDPs portend heightened risk of HF with both reduced and preserved ejection fraction. Gestational diabetes mellitus (GDM) and other APOs such as preterm delivery, small-for-gestational-age delivery, and placental abruption may also confer additional risk for HF development. Possible underlying mechanisms linking APOs to HF include shared upstream risk factors and genetics, accelerated development of cardiometabolic risk factors postpartum, persistent endothelial and microvascular dysfunction, and impaired natriuretic peptide signaling.SummaryHistory of APOs, including HDPs and GDM, confer increased risk for development of HF years after delivery. Further research is needed to define strategies to optimize prepregnancy and postpartum cardiovascular health toward HF prevention.

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Genetic Associations with Placental Proteins in Maternal Serum Identify Biomarkers for Hypertension in Pregnancy

Yan,

Blue,

Truong

et al. 2023

Preprint

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Preeclampsia (PE), a gestational hypertensive disorder, ranks as the second leading cause of maternal mortality worldwide. While PE is considered a multifactorial disease, placental insufficiency is believed to drive its progression. To noninvasively study placental physiology related to adverse pregnancy outcomes (APOs) and predict these outcomes before symptom onset, we measured nine placental protein levels in first- and second-trimester serum samples from 2,352 nulliparous pregnant women in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) study. The proteins analyzed include VEGF, PlGF, ENG, sFlt-1, ADAM-12, PAPP-A, fβHCG, INHA, and AFP. Currently, little is known about the genetic variants contributing to the heritability of these proteins during pregnancy, and no studies have explored the causal relationships between early pregnancy proteins and gestational hypertensive disorders. Our study has three objectives. First, we conducted genome-wide association study (GWAS) of nine placental proteins in maternal serum during the first and second trimesters and the difference between time points to understand how genetics may influence placental proteins in early pregnancy. Second, we examined whether early pregnancy placental proteins are causal factors for PE and gestational hypertension (gHTN). Lastly, we investigated the causal relationship between PE/gHTN and long-term HTN. In conclusion, our study discovered significant genetic associations with placental proteins ADAM-12, VEGF, and sFlt-1, offering insights into their regulation during pregnancy. Mendelian randomization (MR) analyses demonstrated evidence of causal relationships between placental proteins, particularly ADAM-12, and gHTN, potentially informing prevention and treatment strategies. Our findings suggest that placental proteins like ADAM-12 could serve as biomarkers for postpartum HTN risk.

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Genome-wide meta-analysis identifies novel maternal risk variants and enables polygenic prediction of preeclampsia and gestational hypertension

Cited by 4 publications

References 107 publications

Hypertensive disorders of pregnancy and risk of cardiovascular disease: A Mendelian Randomisation study in the UK Biobank

Hypertensive disorders of pregnancy and risk of cardiovascular disease: A Mendelian Randomisation study in the UK Biobank

Adverse pregnancy outcomes and future risk of heart failure

Genetic Associations with Placental Proteins in Maternal Serum Identify Biomarkers for Hypertension in Pregnancy

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