Ryan Marie, Heverin Mark, McLaughlin Russell L, Hardiman Orla
Academic Unit of Neurology, Trinity College Dublin, Dublin, Ireland.
Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
JAMA Neurol. 2019 Nov 1;76(11):1367-1374. doi: 10.1001/jamaneurol.2019.2044.
Heritability describes the proportion of variance in the risk of developing a condition that is explained by genetic factors. Although amyotrophic lateral sclerosis (ALS) is known to have a complex genetic origin, disease heritability remains unclear.
To determine the extent of ALS heritability and assess the association of sex with disease transmission.
DESIGN, SETTING, AND PARTICIPANTS: A prospective population-based parent-offspring heritability study was conducted from January 1, 2008, to December 31, 2017 to assess ALS heritability, and was the first study to assess heritability in the context of known gene mutations of large effect. A total of 1123 incident cases of ALS, diagnosed according to the El Escorial criteria and recorded on the Irish ALS register, were identified. Ninety-two individuals were excluded (non-Irish parental origin [n = 86] and familial ALS [n = 6]), and 1117 patients were included in the final analysis.
Annual age-specific and sex-specific standardized ALS incidence and mortality-adjusted lifetime risk were determined. Sex-specific heritability estimates were calculated for the overall study cohort, for those known to carry the C9orf72 (OMIM 614260) variant, and for those with no known genetic risk.
A total of 32 parent-child ALS dyads were identified during the study period. Affected offspring were younger at the onset of disease (mean age, 52.0 years; 95% CI, 48.8-55.3 years) compared with their parents (mean age, 69.6 years; 95% CI, 62.4-76.9 years; P = .008). Lifetime risk of developing ALS in first-degree relatives of individuals with ALS was increased compared with the general population (1.4% [32 of 2234] vs 0.3% [2.6 of 1000]; P < .001). Mean lifetime heritability of ALS for the overall study cohort was 52.3% (95% CI, 42.9%-61.7%) and 36.9% (95% CI, 19.8%-53.9%) for those with no known genetic risk. Heritability estimates were highest in mother-daughter pairings (66.2%; 95% CI, 58.5%-73.9%).
This population-based study confirms that up to 50% of variance in ALS has a genetic basis, and that the presence of the C9orf72 variant is an important determinant of heritability. First-degree relatives of individuals with ALS without a known genetic basis remain at increased risk of developing ALS compared with the general population. A higher heritability estimate in mother-daughter pairings points to a sex-mediated effect that has been previously unrecognized.
遗传力描述了由遗传因素解释的疾病发生风险中变异的比例。虽然已知肌萎缩侧索硬化症（ALS）有复杂的遗传起源，但疾病遗传力仍不明确。
确定ALS遗传力的程度，并评估性别与疾病传播的关联。
设计、地点和参与者：2008年1月1日至2017年12月31日进行了一项基于人群的前瞻性亲子遗传力研究，以评估ALS遗传力，这是第一项在已知有大效应基因突变背景下评估遗传力的研究。根据埃尔埃斯科里亚尔标准诊断并记录在爱尔兰ALS登记册上的1123例ALS新发病例被识别出来。92人被排除（非爱尔兰父母出身[n = 86]和家族性ALS[n = 6]），1117名患者纳入最终分析。
确定年度年龄和性别特异性标准化ALS发病率以及经死亡率调整的终生风险。计算了整个研究队列、已知携带C9orf72（OMIM 614260）变异者以及无已知遗传风险者的性别特异性遗传力估计值。
研究期间共识别出32对亲子ALS病例。与父母相比，患病后代发病时年龄更小（平均年龄52.0岁；95%CI，48.８-55.3岁），父母平均年龄为69.6岁（95%CI，62.4-76.9岁；P = 0.008）。与一般人群相比，ALS患者一级亲属患ALS的终生风险增加（1.4%[2234人中32例]对0.3%[1000人中2.6例]；P < 0.001）。整个研究队列中ALS的平均终生遗传力为52.3%（95%CI，42.9%-61.7%），无已知遗传风险者为36.9%（95%CI，19.8%-53.9%）。母女配对中的遗传力估计值最高（66.2%；95%CI，58.5%-73.9%）。
这项基于人群的研究证实，高达50%的ALS变异有遗传基础，C9orf72变异的存在是遗传力的一个重要决定因素。与一般人群相比，无已知遗传基础的ALS患者的一级亲属患ALS的风险仍然增加。母女配对中较高的遗传力估计值表明存在一种先前未被认识到的性别介导效应。
