Background Grip strength is a robust indicator of overall health, is moderately heritable, and predicts longevity in older adults. Methods Using genome-wide linkage analysis, we identified a novel locus on chromosome 18p (mega-basepair region: 3.4–4.0) linked to grip strength in 3 755 individuals from 582 families aged 64 ± 12 years (range 30–110 years; 55% women). There were 26 families that contributed to the linkage peak (cumulative logarithm of the odds [LOD] score = 10.94), with 6 families (119 individuals) accounting for most of the linkage signal (LOD = 6.4). In these 6 families, using whole genome sequencing data, we performed association analyses between the 7 312 single nucleotide (SNVs) and insertion deletion (INDELs) variants in the linkage region and grip strength. Models were adjusted for age, age2, sex, height, field center, and population substructure. Results We found significant associations between genetic variants (8 SNVs and 4 INDELs, p < 5 × 10−5) in the Disks Large-associated Protein 1 (DLGAP1) gene and grip strength. Haplotypes constructed using these variants explained up to 98.1% of the LOD score. Finally, RNAseq data showed that these variants were significantly associated with the expression of nearby Myosin Light Chain 12A (MYL12A), Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1), Erythrocyte Membrane Protein Band 4.1 Like 3 (EPB41L3) genes (p < .0004). Conclusions The DLGAP1 gene plays an important role in the postsynaptic density of neurons; thus, it is both a novel positional and biological candidate gene for follow-up studies aimed at uncovering genetic determinants of muscle strength.

中文翻译：

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全基因组连锁和关联分析确定 DLG 相关蛋白 1 是肌肉力量的新型位置和生物学候选基因：长寿家族研究


背景 握力是整体健康状况的有力指标，具有中等遗传性，并预测老年人的寿命。方法使用全基因组连锁分析，我们在染色体 18p （巨碱基对区域：3.4-4.0） 上鉴定了一个与来自 582 个 64 ± 12 岁家庭的 3 755 个个体的握力相关的新位点（范围 30-110 岁;55% 为女性）。有 26 个家系对连锁峰值有贡献 （比值 [LOD] 评分的累积对数 = 10.94），其中 6 个家系 （119 个个体） 占连锁信号的大部分 （LOD = 6.4）。在这 6 个家系中，使用全基因组测序数据，我们进行了连锁区 7 312 个单核苷酸 （SNV） 和插入缺失 （INDELs） 变异与握力之间的关联分析。模型根据年龄、年龄 2 、性别、身高、野中心和种群子结构进行了调整。结果我们发现椎间盘大相关蛋白 1 （DLGAP1） 基因中的遗传变异 （8 个 SNV 和 4 个 INDELs，p < 5 × 10−5） 与握力之间存在显着关联。使用这些变体构建的单倍型解释了高达 98.1% 的 LOD 分数。最后，RNAseq 数据显示，这些变体与附近肌球蛋白轻链 12A （MYL12A） 的表达、染色体柔性铰链结构域包含 1 的结构维持 （SMCHD1）、红细胞膜蛋白带 4.1 Like 3 （EPB41L3） 基因 （p < .0004） 的表达显著相关。结论 DLGAP1 基因在神经元突触后密度中起重要作用;因此，它既是一种新的位置基因，也是生物学候选基因，可用于旨在揭示肌肉力量遗传决定因素的后续研究。