Quantifying the impact of early-life growth adversity on later-life health

Background Early-life growth adversity is important to later-life health, but precision assessment in adulthood is challenging. We evaluated whether the difference between attained and genotype-predicted adult height (“height-GaP”) would associate with prospectively ascertained early-life growth adversity and later-life all-cause and cardiovascular mortality.

Data were first analyzed from the Avon Longitudinal Study of Parents and Children (ALSPAC) and UKBiobank. Genotype-predicted height was calculated using a multi-ancestry polygenic height score. Height-GaP was calculated as the difference between measured and genotype-predicted adult height. Early-life growth conditions were ascertained prospectively via standardized procedures (ALSPAC) and mortality via death register (UKBiobank). Regression models adjusted for age, sex, genotype-predicted height and genetic ancestry. Analyses were replicated in the Dunedin Multidisciplinary Health and Development Study (DMHDS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Findings Among 4,582 ALSPAC participants (median [IQR] age: 24[18-25] years at height-GaP assessment), lower gestational age at birth, greater pre- and post-natal deprivation indices, tobacco smoke exposure and less breastfeeding were associated with larger adult height-GaP deficit (p<0.01). Among 483,385 UKBiobank participants (mean±SD age: 56±8 years at height-GaP assessment), height-GaP deficit was associated with death from all-causes (adjusted hazard ratio comparing highest-to-lowest height-GaP deficit quartile [aHR]:1.25 95%CI:1.21-1.29), atherosclerotic cardiovascular disease (aHR:1.33 95%CI:1.24-1.43) and coronary heart disease (aHR:1.68 95%CI:1.52-1.86). Early- and later-life height-GaP associations replicated in DMHDS and MESA. Interpretation This study introduces a simple index of early-life growth adversity deployable in adulthood to investigate the developmental origins of longevity and improve health equity across the life course. Funding Federal agencies and academic institutions. Competing Interest Statement The authors have declared no competing interest. Funding Statement This research was supported in part by grants from Canadian Institutes of Health Research (193740) and the U.S. National Institutes of Health (R01-HL130506, R01-HL077612). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Genome-wide genotyping data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grants funding and data access policy is available on the ALSPAC website: https://www.bristol.ac.uk/alspac/ The UKBiobank data was accessed using the UK Biobank Resource under application number 773778. A comprehensive list of grant funding and data access policy is available on the UKBiobank website: https://www.ukbiobank.ac.uk/ MESA was supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for "NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)" (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). The information contained herein was derived in part from data provided by the Bureau of Vital Statistics, New York City Department of Health and Mental Hygiene. A full list of participating MESA investigators and institutions and data access policy can be found at http://www.mesa-nhlbi.org. The Dunedin Multidisciplinary Health and Development Research Unit is supported by the New Zealand Health Research Council (Programme Grant 16-604) and has also received funding from the New Zealand Ministry of Business, Innovation and Employment. The study is also supported by the US-National Institute of Aging Grant R01AG032282, and UK Medical Research Council Grant MR/X021149/1. The data access policy can be found at https://dunedinstudy.otago.ac.nz/. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Faculty of Medicine and Health Sciences Research Ethics Board of McGill University gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Due to legal and privacy reasons, participant-level data that support the findings of the study are managed under restricted access and available upon reasonable request from the ALSPAC, Dunedin, UKBiobank and MESA cohort study committees. https://www.bristol.ac.uk/alspac/ https://dunedinstudy.otago.ac.nz/for-investigators/policy-statement-code-of-practic