Files S3 and S4. Filtered .map and .ped files (563,042 SNPs) for 102 BCHF matched case-control pairs, Filename: BCHF102pairsHD770Filtered (20.9 and 438.2 Mb, respectively.)

Bovine congestive heart failure (BCHF) has become increasingly prevalent among feedlot cattle in the Western Great Plains of North America with up to 7% mortality in affected herds. BCHF is an untreatable complex condition involving pulmonary hypertension that culminates in right ventricular failure and death. Genes associated with BCHF in feedlot cattle have not been previously identified. Our aim was to search for genomic regions associated with this disease. A retrospective, matched case-control design with 102 clinical BCHF cases and their unaffected penmates was used in a genome-wide association study. Paired nominal data from approximately 560k filtered single nucleotide polymorphisms (SNPs) were analyzed with McNemar’s test. The most significant genome-wide association was in the arrestin domain-containing 3 protein gene (ARRDC3), followed by the nuclear factor IA gene (NFIA, mid-p-values, 1x10E-8 and 2x10E-7, respectively). Animals with homozygous risk alleles at either gene were approximately 8-fold more likely to have BCHF than their matched penmates without those risk alleles (CI95 = 3-17). Animals with homozygous risk alleles at both genes were 28-fold more likely to have BCHF than all others (p-value = 1x10E-7, CI95 = 4-206). A linked missense variant in ARRDC3 (C182Y) represents a potential functional variant since C182 is conserved among all other jawed vertebrate species observed. A DNA test with two markers showed 29% of 273 BCHF cases had homozygous risk alleles in both genes, compared to 2.5% in 198 similar unaffected feedlot cattle. This DNA test may be useful for identifying feedlot animals with the highest risk for BCHF in the environments described here. Although pathogenic roles for ARRDC3 and NFIA variants associated with BCHF are unknown, their discovery facilitates classifying animals by genetic risk and allows cattle producers to make informed decisions for selective breeding and animal health management.牛充血性心力衰竭（Bovine congestive heart failure, BCHF）已在北美西部大平原的育肥牛群中愈发普遍，染病牛群的死亡率可达7%。BCHF是一种无法治愈的复杂病症，涉及肺动脉高压，最终会引发右心衰竭乃至死亡。此前尚未有研究鉴定出与育肥牛BCHF相关的基因。本研究旨在探寻与该疾病相关的基因组区域。本研究采用回顾性配对病例对照设计，纳入102例临床BCHF病例及其未患病的同栏同伴，开展全基因组关联分析。对约56万个经过滤的单核苷酸多态性（single nucleotide polymorphisms, SNPs）的配对名义数据，采用麦克尼玛检验（McNemar’s test）进行分析。全基因组范围内最显著的关联位点位于抑制蛋白结构域包含3蛋白基因（arrestin domain-containing 3 protein gene, ARRDC3），其次是核因子IA基因（nuclear factor IA gene, NFIA），二者的中位p值分别为1×10^-8和2×10^-7。携带任一基因纯合风险等位基因的个体，患BCHF的风险约为未携带此类风险等位基因的配对同栏同伴的8倍（95%置信区间：3~17）。同时携带两个基因纯合风险等位基因的个体，患BCHF的风险约为其他所有个体的28倍（p值=1×10^-7，95%置信区间：4~206）。ARRDC3基因中存在一个连锁的错义变异（C182Y），由于C182在所有已观测到的有颌脊椎动物中均保守，该变异可能是功能性变异。针对两个标记的DNA检测显示，273例BCHF病例中有29%在两个基因中均携带纯合风险等位基因，而在198例相似的未患病育肥牛中这一比例仅为2.5%。本研究所用的DNA检测或可用于在上述环境条件下，识别BCHF风险最高的育肥牛个体。尽管目前尚不清楚ARRDC3和NFIA的变异与BCHF的致病机制，但相关变异的发现有助于根据遗传风险对牛只进行分类，并使肉牛养殖户能够为选择性育种和动物健康管理做出明智决策。