{"doi":"10.1093/eurjpc/zwad296","title":"Genetically predicted gestational age and birth weight are associated with cardiac and pulmonary vascular remodelling in adulthood","abstract":"Preterm birth (<37 weeks gestation) and small for gestational age (SGA; <10th percentile) each affect ∼10–15% of live births worldwide. Individuals born at an early gestational age (GA) and/or low birth weight (BW) more often develop pulmonary hypertension or heart failure later in life, potentially due to pulmonary vascular and cardiac remodelling from birth to adulthood.1–3 However, most evidence linking these factors to cardiopulmonary remodelling stems from observational studies1–3 that were potentially affected by sociodemographic confounding. To mitigate the cardiopulmonary impact of early GA and low BW, it is necessary to understand whether each factor contributes causally to cardiovascular remodelling in adulthood. Here, we tested the associations of genetically predicted GA and BW Z-score (adjusted for GA) on measures of cardiac and pulmonary arterial (PA) structure and function using Mendelian randomization (MR). We used two-sample MR to infer causal associations of GA and BW Z-score with cardiac and PA structure and function. Mendelian randomization tests whether an exposure–outcome relationship is causal by leveraging the random assortment of genetic variants as instrumental variables. Single-nucleotide variants (SNVs) associated with BW Z-score and GA were identified in 84 689 and 26 836 European-ancestry participants, respectively, from the Early Growth Genetics (EGG) Consortium.4,5 The EGG Consortium is a large-scale collaboration including >40 genotyped cohorts with data on birth characteristics such as BW (pooled mean: 3.45 ± 0.57 kg) and GA (pooled mean: 39.8 ± 1.8 weeks).4,5 Single-nucleotide variants for cardiac and PA structure and function were extracted from genome-wide association studies including up to 43 230 European-ancestry UK Biobank participants who underwent cardiac magnetic resonance (CMR) imaging.6–9 Structural measures were indexed to body surface area (using the Mosteller8 or Dubois6,7 formulas). There was no sample overlap between exposure and outcome cohorts. Since only one SNV reached genome-wide significance (P < 5 × 10−8) for GA, primary analyses utilized a lenient significance threshold (P < 5 × 10−3) using the robust adjusted profile score (MR-RAPS) method—a method that accommodates sub-genome-wide significant variants while accounting for horizontal pleiotropy (i.e. effects of the variants through pathways other than the exposure of interest). Correlated SNVs (linkage disequilibrium R² < 0.001) were clumped within regions of 10 Mb. Mean F-statistics for BW Z-score and GA were 10.7 and 10.8, respectively. Sensitivity analyses used the inverse-variance-weighted, median-based, mode-based, and MR-Egger methods. Additional sensitivity analyses used a more stringent P-value threshold (P < 5 × 10−6) and tested for horizontal pleiotropy using the MR-Egger intercept test. Associations were considered robust if the primary analysis was statistically significant, all sensitivity analyses were directionally consistent, and there was no evidence of horizontal pleiotropy (MR-Egger intercept P > 0.05). Due to strong correlation among measures of cardiac and PA structure and function,8 we used a false discovery rate Q-value < 0.10 to determine statistical significance in primary analyses. In primary analyses, lower genetically predicted BW Z-score was associated with smaller ascending aortic (AA) and right atrial (RA) dimensions, whereas earlier GA was associated with decreased PA, right ventricular (RV), and left atrial size (Figure 1). Sensitivity analyses demonstrated robust associations of lower genetically predicted BW Z-score with smaller AA diameter index and RA maximal volume index; earlier GA was robustly associated with smaller systolic PA to AA diameter ratio, RV end-diastolic volume index, and RV stroke volume index (Figure 2). All associations with structural parameters were directionally consistent with estimates using the same parameters not indexed for body size: lower genetically pr","journal":"European Journal of Preventive Cardiology","year":2023,"id":385360,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":700293,"name":"Maddalena Ardissino","orcid":"0000-0002-2654-8117","position":1,"is_corresponding":false},{"id":889,"name":"Victor Nauffal","orcid":"0000-0001-7199-299X","position":2,"is_corresponding":false},{"id":552483,"name":"Shaan Khurshid","orcid":"0000-0002-2840-4539","position":3,"is_corresponding":false},{"id":902,"name":"James P. Pirruccello","orcid":"0000-0001-6088-4037","position":4,"is_corresponding":false},{"id":896,"name":"Patrick T. Ellinor","orcid":"0000-0002-2067-0533","position":5,"is_corresponding":false},{"id":31221,"name":"Adam J. Lewandowski","orcid":"0000-0002-4978-8965","position":6,"is_corresponding":false},{"id":24665,"name":"Pradeep Natarajan","orcid":"0000-0001-8402-7435","position":7,"is_corresponding":false},{"id":373536,"name":"Michael C. Honigberg","orcid":"0000-0001-8630-5021","position":8,"is_corresponding":false},{"id":991228,"name":"Art Schuermans","orcid":"0000-0001-8146-9692","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:17:48.629718Z","pmid":"37694688","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}