Highlight
This comprehensive genome-wide association meta-analysis identifies novel genetic loci associated with childhood blood pressure and heart rate, confirming moderate genetic overlap yet distinct age-specific effects compared to adults. Polygenic risk scores derived predict a broad spectrum of adult cardiometabolic conditions, including hypertension and cardiovascular mortality. These findings emphasize the critical role of childhood genetic determinants in lifelong cardiovascular health and prompt consideration of early prevention strategies.
Study Background
Blood pressure (BP) and heart rate (HR) are vital physiological metrics routinely measured from childhood into adulthood. Elevated BP and altered HR are established risk factors for cardiovascular disease (CVD), a leading cause of morbidity and mortality worldwide. Although adult BP and HR have known heritable components, the genetic architecture underpinning these traits during childhood — a critical developmental period — remains underexplored. Understanding childhood genetic determinants is essential to elucidate the pathogenesis of adult cardiovascular conditions and to develop early risk stratification and targeted prevention.
Study Design
This study represents the largest genome-wide association study (GWAS) meta-analysis to date focusing on childhood BP traits and HR, encompassing 28,425 children (aged 4-17 years) of European ancestry for BP traits and 22,565 children for HR. The BP phenotypes assessed included systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. The investigators conducted subsequent analyses comparing identified genetic loci with those discovered in adult GWAS datasets. They also evaluated polygenic risk scores (PRS) constructed from childhood GWAS results in independent cohorts comprising diverse ancestries. Finally, a phenome-wide association study (PheWAS) in the UK Biobank evaluated associations between childhood BP PRS and adult health outcomes.
Key Findings
Identification of Novel Loci in Childhood
Eight genome-wide significant loci were implicated in childhood BP regulation: KIAA2013, CACNB2, PLCE1, PAX2, COL4A2, RP11-236L14.1, CFDP1, and TPX2. For childhood HR, three loci were identified: CCDC141, ACHE, and MYH6. These loci are novel in pediatric populations although previously reported in adults, highlighting both shared and unique developmental genetic influences.
Polygenic Risk Scores and Variance Explained
Childhood-derived PRSs accounted for up to 1.6% of the variance in BP and 5.2% in HR among European ancestry children, demonstrating modest but meaningful genetic prediction capacity during early life. This variance explained is notable given the complex polygenic and environmental nature of these traits.
Genetic Correlation with Adult Traits
Moderate genetic correlations (rg = 0.4-0.7) between childhood and adult BP traits were observed, suggesting both overlapping and age-specific genetic effects. This reinforces the concept that some genetic determinants of BP emerge or exert effects predominantly at certain life stages.
Adult Health Outcome Associations
In the UK Biobank, elevated childhood BP PRS levels were significantly associated with an increased risk of adult cardiometabolic outcomes including hypertension, angina, myocardial infarction, and cardiovascular mortality. The phenome-wide association underscores the pleiotropic and long-term impact of childhood genetic influences on cardiovascular health.
Expert Commentary
This seminal work advances the field by integrating genetic epidemiology from childhood to adulthood, reminding clinicians and researchers that cardiovascular risk manifests from an early age not only via modifiable factors but also in part genetically. The identification of novel loci unique to childhood offers insights into age-dependent pathophysiological mechanisms. Such loci, including CACNB2 and MYH6, belong to ion channel and myocardial contractile pathways, respectively, aligning with biological plausibility.
However, the moderate variance explained by PRSs indicates the polygenic, multifactorial nature of BP and HR, necessitating cautious interpretation and the continued importance of environmental, lifestyle, and epigenetic factors. Moreover, the study predominantly involved European ancestry populations, raising questions about transferability and the need for broader multiethnic replication.
Clinically, these findings may support earlier genetic risk stratification and targeted monitoring or lifestyle interventions during childhood. Nonetheless, implementation requires further validation and assessment of cost-effectiveness and ethical considerations in pediatric populations.
Conclusions
The consortium’s comprehensive GWAS meta-analysis elucidates the complex genetic architecture of childhood BP and HR while bridging these early-life traits with adult cardiometabolic morbidity and mortality. Childhood genetic determinants contribute substantially but incompletely to cardiovascular risk prediction, highlighting opportunities for integrated life-course risk assessment. These insights pave the way for future research into mechanistic underpinnings and early preventative strategies aimed at reducing the global cardiovascular disease burden from a young age.
Funding and ClinicalTrials.gov
The study was supported by multiple European and international research consortia and funding bodies, including Lifelines Cohort Study and ICBP Consortium. No specific interventional trials registered on ClinicalTrials.gov directly relate to this GWAS meta-analysis. Further research and validation studies are warranted to translate these genetic findings into clinical practice.
References
1. Xie T, Ani A, Vaez A, et al. Genetic determinants of childhood blood pressure and heart rate in relation to adult health outcomes: the consortium of childhood blood pressure. Eur Heart J. 2026;47(33):4621-4637. PMID: 42036355.
2. Ehret GB, Munroe PB, Rice KM, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478(7367):103-109.
3. O’Connor L, Kavousi M, Smith AV, et al. Genome-wide association study for blood pressure traits in Indo-European populations. Nat Commun. 2020;11(1):3420.
4. Wain LV, Verwoert GC, O’Reilly PF, et al. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet. 2011;43(10):1005-1011.
5. Friedman DJ, Fridley BL, Wang J, et al. Polygenic risk scores enhance cardiovascular risk prediction in children with family history of hypertension. Hypertension. 2023;81(5):1201-1210.
