Genetic factors play a major role in frontotemporal dementia (FTD). The majority of FTD cannot be genetically explained yet and it is likely that there are still FTD risk loci to be discovered. Common variants have been identified with genome-wide association studies (GWAS), but these studies have not systematically searched for rare variants. To identify rare and new common variant FTD risk loci and provide more insight into the heritability of C9ORF72-related FTD, we performed a GWAS consisting of 354 FTD patients (including and excluding N = 28 pathological repeat carriers) and 4209 control subjects. The Haplotype Reference Consortium was used as reference panel, allowing for the imputation of rare genetic variants. Two rare genetic variants nearby C9ORF72 were strongly associated with FTD in the discovery (rs147211831: OR = 4.8, P = 9.2 × 10⁻⁹, rs117204439: OR = 4.9, P = 6.0 × 10⁻⁹) and replication analysis (P < 1.1 × 10⁻³). These variants also significantly associated with amyotrophic lateral sclerosis in a publicly available dataset. Using haplotype analyses in 1200 individuals, we showed that these variants tag a sub-haplotype of the founder haplotype of the repeat expansion that was previously found to be present in virtually all pathological C9ORF72 G₄C₂ repeat lengths. This new risk haplotype was 10 times more likely to contain a C9ORF72 pathological repeat length compared to founder haplotypes without one of the two risk variants (~22% versus ~2%; P = 7.70 × 10⁻⁵⁸). In haplotypes without a pathologic expansion, the founder risk haplotype had a higher number of repeats (median = 12 repeats) compared to the founder haplotype without the risk variants (median = 8 repeats) (P = 2.05 × 10⁻²⁶⁰). In conclusion, the identified risk haplotype, which is carried by ~4% of all individuals, is a major risk factor for pathological repeat lengths of C9ORF72 G₄C₂. These findings strongly indicate that longer C9ORF72 repeats are unstable and more likely to convert to germline pathological C9ORF72 repeat expansions.

遗传因素在额颞叶痴呆（FTD）中起主要作用。大多数 FTD 尚无法从基因上解释，很可能仍有 FTD 风险位点有待发现。已通过全基因组关联研究 (GWAS) 确定了常见变体，但这些研究并未系统地搜索稀有变体。为了识别罕见和新的常见变异 FTD 风险基因座并提供对C9ORF72相关 FTD遗传力的更多见解，我们进行了由 354 名 FTD 患者（包括和不包括N  = 28 名病理重复携带者）和 4209 名对照受试者组成的 GWAS。Haplotype Reference Consortium 被用作参考面板，允许对稀有遗传变异进行估算。C9ORF72附近的两个罕见基因变异在发现（rs147211831：OR = 4.8，P  = 9.2 × 10 ^-9，rs117204439：OR = 4.9，P  = 6.0 × 10 ^-9）和复制分析（P  < 1.1 × 10 ^-3）中与 FTD 密切相关。在公开可用的数据集中，这些变体也与肌萎缩侧索硬化显着相关。通过对 1200 名个体进行单倍型分析，我们发现这些变体标记了重复扩增的创始单倍型的亚单倍型，之前发现该亚单倍型几乎存在于所有病理性C9ORF72 G ₄ C ₂重复长度中。这种新的风险单倍型包含C9ORF72的可能性高 10 倍与没有两种风险变异之一的创始人单倍型相比的病理重复长度（~22％对~2％；P  = 7.70 × 10 ^-58）。在没有病理扩展的单倍型中，与没有风险变异的创始人单倍型（中位数 = 8 重复）相比，创始人风险单倍型具有更高的重复数（中位数 = 12 重复）（P  = 2.05 × 10 ^-260）。总之，约 4% 的个体携带已确定的风险单倍型，是C9ORF72 G ₄ C ₂病理重复长度的主要风险因素。这些发现强烈表明更长的 C9ORF72重复是不稳定的，更有可能转化为种系病理性C9ORF72重复扩增。