Beijing Da Xue Xue Bao Yi Xue Ban. 2026 Jun 18;58(3):528-535.
ABSTRACT
OBJECTIVE: To evaluate the genetic nurture effect of parental genotypes on the risk of ischemic stroke (IS) in offspring and to elucidate the parental origin-specific differences in this effect.
METHODS: This study utilized data from the “Family Cohort of Common Chronic Non-communicable Diseases in Rural Areas of Northern China”. A total of 530 core families and sibling pairs were selected, comprising 1 005 offspring. Single nucleotide polymorphisms (SNPs) within the CTNNA gene family (CTNNA1, CTNNA2 and CTNNA3) were detected. Using offspring as the unit of analysis, parental non-transmitted alleles were inferred based on Mendelian inheritance principles. Rigorous quality control was implemented for genotype imputation, ensuring high reliability of the inferred data. Linear mixed-effects models were constructed to estimate the genetic nurture effect of non-transmitted alleles on offspring IS. These models compared differences between genetic nurture effects and individual genetic effects, distinguished between paternal and maternal effects, and calculated the statistic η to assess the relative magnitude of parental effects.
RESULTS: A total of 1 005 offspring from 530 families were included, comprising 308 IS patients (30.6%) with a mean age of 56.3 years. Sixteen independent SNPs associated with IS genetic nurture effects were identified (9 in CTNNA2, 6 in CTNNA3, and 1 in CTNNA1). The effect sizes ranged from -0.282 to 0.480, with rs117741773 (CTNNA2) showing the strongest effect (0.480, 95%CI: 0.278-0.682). Only four of these SNPs exhibited concurrent individual genetic effects, which acted in the opposite direction to the genetic nurture effects. Parent-of-origin specific analysis revealed that 12 SNPs exhibited genetic nurture effects from a single origin: 4 showed exclusively paternal effects (effect size: -0.298 to 0.945; η: 1.21 to 63.83), and 8 showed exclusively maternal effects (effect size: -0.489 to 0.602; η: 0.03 to 0.44).
CONCLUSION: This study provides evidence that multiple IS susceptibility loci within the CTNNA gene family exhibit significant genetic nurture effects. The findings highlight the complex interplay between inherited genetics and the family environment. The heterogeneity of these effects based on parental origin underscores the significant role of parent-specific genetic nurture in the etiology of IS, offering new insights for understanding the missing heritability in stroke genetics.
PMID:42287047
