Data from: Genome-wide association analysis in dogs implicates 99 loci as risk variants for anterior cruciate ligament rupture

Anterior cruciate ligament (ACL) rupture is common condition that can be devastating and life changing, particularly in young adults. A non-contact mechanism is typical. Second ACL ruptures through rupture of the contralateral ACL or rupture of a graft repair is also common. Risk of rupture is increased in females. ACL rupture is also common in dogs. Disease prevalence exceeds 5% in several dog breeds, ~100 fold higher than human beings. We provide insight into the genetic etiology of ACL rupture by genome-wide association study (GWAS) in a high-risk breed using 98 case and 139 control Labrador Retrievers. We identified 129 single nucleotide polymorphisms (SNPs) within 99 risk loci. Associated loci (P<5.0E-04) explained approximately half of phenotypic variance in the ACL rupture trait. Two of these loci were located in uncharacterized or non-coding regions of the genome. A chromosome 24 locus containing nine genes with diverse functions met genome-wide significance (P=3.63E-0.6). GWAS pathways were enriched for c-type lectins, a gene set that includes aggrecan, and a gene set encoding membrane transport proteins with a variety of physiological functions. Genotypic risk estimated for each dog based on the risk contributed by each GWAS locus showed clear separation of ACL rupture cases and controls. Power analysis of the GWAS data set estimated that ~172 loci explain the genetic contribution to ACL rupture in the Labrador Retriever. Heritability was estimated at 0.48. We conclude ACL rupture is a moderately heritable highly polygenic complex trait. Our results implicate c-type lectin pathways in ACL homeostasis.前交叉韧带（Anterior cruciate ligament, ACL）断裂是一种常见且具有破坏性、会改变患者生活的疾病，尤其好发于青年人群，其典型致病机制为非接触性损伤。继发前交叉韧带断裂，包括对侧前交叉韧带断裂或移植物修复后再断裂的情况也较为常见。女性群体的前交叉韧带断裂风险更高。前交叉韧带断裂在犬类中同样高发，多个犬品种的该病患病率超过5%，较人类高出约100倍。 本研究针对高风险犬品种，以98例患病拉布拉多猎犬与139例健康对照犬为研究对象，通过全基因组关联分析（genome-wide association study, GWAS）解析前交叉韧带断裂的遗传病因。我们在99个风险位点内鉴定出129个单核苷酸多态性（single nucleotide polymorphisms, SNPs）。关联位点（P<5.0×10^-4）可解释前交叉韧带断裂表型约一半的变异量。其中2个位点位于基因组未注释区域或非编码区。位于24号染色体、包含9个功能各异基因的位点达到全基因组显著性水平（P=3.63×10^-6）。 全基因组关联分析富集到的通路包括C型凝集素通路，该基因集包含聚集蛋白聚糖，以及编码具有多种生理功能的膜转运蛋白的基因集。基于每个全基因组关联分析位点的风险贡献，对每只犬进行的基因型风险评估可清晰区分前交叉韧带断裂病例与健康对照。对本全基因组关联分析数据集的效力分析估计，约172个位点可解释拉布拉多猎犬前交叉韧带断裂的遗传贡献。该性状的遗传力估计值为0.48。 我们得出结论：前交叉韧带断裂是一种中度遗传力的高度多基因复杂性状。本研究结果提示C型凝集素通路参与前交叉韧带的稳态维持。