Figueroa K P, Coon Hilary, Santos Nieves, Velazquez Luis, Mederos Luis Almaguer, Pulst Stefan-M
Department of Neurology (K.P.F., S.-M.P.), Department of Psychiatry (H.C.), University of Utah, Salt Lake City; Department of Surgery (N.S.), University of Miami, FL; and Center for the Research and Rehabilitation of Hereditary Ataxias (L.V., L.A.M.), Holguin, Cuba.
Neurol Genet. 2017 May 15;3(3):e155. doi: 10.1212/NXG.0000000000000155. eCollection 2017 Jun.
To examine heritability of the residual variability of spinocerebellar ataxia type 2 (SCA2) age at onset (AO) after controlling for CAG repeat length.
From 1955 to 2001, dates of birth, CAG repeat lengths, AO, sex, familial inheritances, and clinical manifestations were collected for a large Cuban SCA2 cohort of 382 affected individuals, including 129 parent-child pairs and 69 sibships. Analyses were performed with log-transformed AO in the GENMOD procedure to predict AO using repeat length, taking into account family structure. Because all relationships were first degree, the model was implemented with an exchangeable correlation matrix. Familial correlations were estimated using the Pedigree Analysis Package to control for similarity due to genetic relatedness.
For the entire sample, the mutant CAG repeat allele explained 69% of AO variance. When adjusted for pedigree structure, this decreased to 50%. Evidence for imprinting or sex-specific effects of the CAG repeat on AO was not found. For the entire sample, we determined an upper bound for heritability of the residual variance of 33% ( = 0.008). Heritability was higher in sib-sib pairs, especially in female sib-sib pairs, than in parent-child pairs.
We established that a large proportion of AO variance in SCA2 was determined by genetic modifiers in addition to CAG repeat length. The genetic structure of heritability of the residual AO variance was surprisingly similar to Huntington disease, suggesting the presence of recessive modifying alleles and possibly X-chromosome-linked modifiers.
在控制CAG重复长度后，研究2型脊髓小脑共济失调（SCA2）发病年龄（AO）的残余变异性的遗传力。
从1955年到2001年，收集了古巴一个由382名受影响个体组成的大型SCA2队列的出生日期、CAG重复长度、AO、性别、家族遗传和临床表现，其中包括129对亲子对和69个同胞组。在GENMOD程序中对经对数转换的AO进行分析，以重复长度为预测因子，同时考虑家族结构。由于所有关系均为一级亲属关系，因此模型采用可交换相关矩阵实现。使用谱系分析软件包估计家族相关性，以控制由于遗传相关性导致的相似性。
对于整个样本，突变的CAG重复等位基因解释了AO方差的69%。在根据谱系结构进行调整后，这一比例降至50%。未发现CAG重复对AO有印记或性别特异性影响的证据。对于整个样本，我们确定残余方差遗传力的上限为33%（P = 0.008）。同胞对中的遗传力高于亲子对，尤其是女性同胞对。
我们确定，除了CAG重复长度外，SCA2中很大一部分AO方差是由遗传修饰因子决定的。残余AO方差遗传力的遗传结构与亨廷顿病惊人地相似，表明存在隐性修饰等位基因以及可能的X染色体连锁修饰因子。
