CTNNA 基因家族遗传培育效应与缺血性脑卒中的关联分析

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

摘要

目的：评估亲代基因型对子代缺血性脑卒中（ischemic stroke，IS）风险的遗传培育效应，并解析该效应的父源与母源差异。方法：依托＂北方农村地区居民常见慢性非传染性疾病家系队列研究＂，选取核心家系、同胞对等，检测 CTNNA 基因家族（CTNNA1、CTNNA2、CTNNA3）的单核苷酸多态性（single nucleotide polymorphisms，SNPs）。以子代为单位推断亲代未传递给子代的等位基因，构建线性混合效应模型，评估亲代未传递等位基因对子代 IS 的遗传培育效应，并对比其与个体遗传效应的差异，区分父源、母源效应，同时构建统计量 η 评估两者的相对大小。结果：共纳入 530 个家系的1005名子代，其中 IS 患者共 308 例（30.6%），平均年龄 56.3 岁。共识别了 16 个具有IS 遗传培育效应的独立 SNPs(9 个位于 CTNNA2,6 个位于 CTNNA3,1 个位于 CTNNA1) ，效应值为 -0.282∼0.480 ，rs 117741773 （CTNNA2）的效应最强（0.480,95\%CI:0.278∼0.682）；其中，仅 4 个 SNPs 兼具个体遗传效应，且方向与遗传培育效应相反。亲本特异性分析显示，12个 SNPs 呈单一亲本遗传培育效应，4个仅表现为父源效应（效应值：$-0.298\sim 0.945,\mathit{\eta }:1.21\sim 63.83$）， 8 个仅表现为母源效应（效应值：-0.489∼0.602,η:0.03∼0.44）。结论：CTNNA 基因家族中存在多个具有遗传培育效应的 IS 易感位点，且不同亲本来源效应存在异质性，提示亲本特异性遗传培育效应在 IS 病因中具有重要作用。

Abstract

Objective：To evaluate the genetic nurture effect of parental genotypes on the risk of ische- mic 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 1005 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，distin- guished between paternal and maternal effects，and calculated the statistic η to assess the relative magni- tude of parental effects. Results：A total of 1005 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.

关键词

遗传培育效应 / 亲本特异性 / 缺血性卒中 / CTNNA 基因家族 / 基因-环境相互作用

Key words

Genetic nurture effect / Parent-of-origin specific / Ischemic stroke / CTNNA gene family / Gene-environment interactions

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