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Journal of Peking University (Health Sciences) ›› 2026, Vol. 58 ›› Issue (3): 528-535. doi: 10.19723/j.issn.1671-167X.2026.03.012

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Association analysis between genetic nurturing effects of CTNNA gene family and ischemic stroke

Jingxian WU1, Liuyan ZHENG1, Huan YU1, Huairong WANG1, Shuting XIE1, Yalin CHEN1, Teng LI1, Mengying WANG2,3, Xueying QIN1,2, Tao WU1,2, Dafang CHEN1,2, Yiqun WU1,2,*(), Yonghua HU1,2   

  1. 1. Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China
    2. Key Laboratory of Epidemiology of Major Disease (Peking University), Ministry of Education, Beijing 100191, China
    3. Department of Nutrition and Food Hygiene, Peking University School of Public Health, Beijing 100191, China
  • Received:2026-03-10 Online:2026-06-18 Published:2026-04-09
  • Contact: Yiqun WU

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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.

Key words: Genetic nurture effect, Parent-of-origin specific, Ischemic stroke, CTNNA gene family, Gene-environment interactions

CLC Number: 

  • R181.33

Table 1

Basic characteristics of offsprings"

Items Offsprings without IS
(n=697)		 Offsprings with IS
(n=308)		 Total Offsprings
(n=1 005)		 P value
Age/years, $\bar x \pm s$ 54.5±10.8 60.5±7.8 56.3±10.4 < 0.001
Gender, n (%) 0.002
  Male 386 (55.4) 203 (65.9) 589 (58.6)
  Female 311 (44.6) 105 (34.1) 416 (41.4)
Marital status, n (%) 0.961
  Married 612 (89.3) 267 (89.0) 879 (89.2)
  Other status 73 (10.7) 33 (11.0) 106 (10.8)
Educational status, n (%) < 0.001
  Primary school and below 234 (34.1) 148 (48.8) 382 (38.6)
  Junior high school 313 (45.6) 121 (39.9) 434 (43.9)
  Senior high school and above 139 (20.3) 34 (11.2) 173 (17.5)
Hypertension, n (%) 340 (57.1) 217 (73.3) 557 (62.4) < 0.001
Diabetes mellitus, n (%) 157 (26.7) 89 (29.7) 246 (27.7) 0.393
Hyperlipidemia, n (%) 181 (34.9) 132 (50.4) 313 (40.1) < 0.001
BMI/(kg/m2), $\bar x \pm s$ 26.3±3.8 26.3±3.6 26.3±3.5 0.780

Table 2

Sixteen SNPs with genetic nurture effects on IS"

SNPs A1 A2 MAF βnT (95%CI) P value
CTNNA1
  rs76210266 T C 0.011 0.362 (0.108, 0.615) 5.21×10-3
CTNNA2
  rs117741773 A G 0.011 0.480 (0.278, 0.682) 3.29×10-6
  rs78592910 A C 0.011 0.361 (0.136, 0.586) 1.64×10-3
  rs55767232 G A 0.019 0.243 (0.067, 0.419) 6.84×10-3
  rs868032 C T 0.496 0.065 (0.020, 0.111) 4.68×10-3
  rs546179372 T TA 0.355 0.065 (0.016, 0.115) 9.90×10-3
  rs6547309 C A 0.408 0.068 (0.019, 0.116) 5.58×10-3
  rs149752934 T C 0.019 -0.282 (-0.452, -0.113) 1.11×10-3
  rs181654218 T C 0.016 -0.272 (-0.465, -0.079) 5.71×10-3
  rs10166591 C T 0.373 -0.063 (-0.111, -0.016) 8.67×10-3
CTNNA3
  rs16924512 G A 0.013 0.239 (0.067, 0.412) 6.50×10-3
  rs79767344 C T 0.027 0.206 (0.062, 0.351) 5.21×10-3
  rs78184651 C T 0.015 -0.267 (-0.460, -0.074) 6.79×10-3
  rs78365177 T C 0.021 -0.250 (-0.417, -0.083) 3.37×10-3
  rs78279947 C G 0.020 -0.238 (-0.416, -0.061) 8.56×10-3
  rs139947562 A G 0.026 -0.233 (-0.380, -0.085) 2.01×10-3

Figure 1

Genetic nurture effects, individual genetic effects and total genetic effects of 16 SNPs on IS IS, ischemic stroke; SNPs, single nucleotide polymorphisms."

Figure 2

Paternal and maternal genetic nurture effects of 16 SNPs on IS IS, ischemic stroke; SNPs, single nucleotide polymorphisms; η, the ratio of the absolute values of paternal genetic nurture effect to maternal genetic nurture effect."

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