Precision Medicine Center, Future Innovation Research Division, Seoul National University Bundang Hospital, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do, 13620, South Korea.
Department of Pathology, Seoul National University Bundang Hospital, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do, 13620, South Korea.
BMC Genomics. 2023 Dec 18;24(1):787. doi: 10.1186/s12864-023-09903-3.
We performed comprehensive association analyses of common high-confidence gnomAD-reported copy number deletions (CNDs) with 60 quantitative traits from UK10K consortium WGS data.
The study made use of data generated by the UK10K Consortium. UK10K consortium WGS data consist of TwinsUK (n = 1754, middle-aged females) and ALSPAC (n = 1867, birth to adolescence) cohorts. UK10K consortium called 18,739 CNDs (hg19) with GenomeSTRiP software. After filtering out variants with minor allele frequency < 0.05 or HWE P < 1.0 × 10, 1222 (TwinsUK) and 1211 (ALSPAC) CNDs remained for association analyses with 60 normalized quantitative traits.
We identified 23 genome-wide significant associations at 13 loci, among which 2 associations reached experiment-wide significance. We found that two common deletions in chromosome 4, located between WDR1 and ZNF518B (23.3 kb, dbVar ID:nssv15888957, 4:10211262-10,234,569 and 9.8 kb, dbVar ID:nssv15888975, 4:10392422-10,402,191), were associated with uric acid levels (P = 5.23 × 10 and 2.29 × 10, respectively). We also discovered a novel deletion spanning chromosome 18 (823 bp, dbVar ID: nssv15841628, 8:74347187-74,348,010) associated with low HDL cholesterol levels (P = 4.15 × 10). Additionally, we observed two red blood cell traits-associated loci with genome-wide significance, a 13.2 kb deletion in 7q22.1 (nssv15922542) and a 3.7 kb deletion in 12q24.12 (nssv15813226), both of which were located in regions previously reported to be associated with red blood cell traits. Two deletions in 11q11 (nssv15803200 and nssv15802240), where clusters of multiple olfactory receptor genes exist, and a deletion (nssv15929560) upstream to DOCK5 were associated with childhood obesity. Finally, when defining Trait-Associated copy number Deletions (TADs) as CNDs with phenotype associations at sub-threshold significance (P < 10), we identified 157 (97.5%) out of 161 TADs in non-coding regions, with a mean size of 4 kb (range: 209 - 47,942 bp).
We conducted a reanalysis of the UK10K Whole Genome Sequencing cohort, which led to the identification of multiple high confidence copy number deletions associated with quantitative traits. These deletions have standard dbVar IDs and replicate previous findings, as well as reveal novel loci that require further replication studies.
我们对 UK10K 全基因组测序队列进行了重新分析，鉴定了多个与定量性状相关的高可信度拷贝数缺失。
本研究利用了 UK10K 联盟的数据。UK10K 联盟的 WGS 数据包括 TwinsUK（n=1754，中年女性）和 ALSPAC（n=1867，出生至青春期）队列。UK10K 联盟使用 GenomeSTRiP 软件对 18739 个 CNDs（hg19）进行了编号。在过滤掉等位基因频率<0.05 或 HWE P<1.0×10 的变体后，1222 个（TwinsUK）和 1211 个（ALSPAC）CNDs 仍然保留下来，用于与 60 个标准化的定量性状进行关联分析。
我们在 13 个位点鉴定到 23 个全基因组显著关联，其中 2 个关联达到了实验全基因组显著性。我们发现，4 号染色体上两个常见的缺失，分别位于 WDR1 和 ZNF518B 之间（23.3kb，dbVar ID：nssv15888957，4：10211262-10234569 和 9.8kb，dbVar ID：nssv15888975，4：10392422-10402191），与尿酸水平相关（P=5.23×10和 2.29×10）。我们还发现了一个跨越 18 号染色体的新缺失（823bp，dbVar ID：nssv15841628，8：74347187-74348010），与低 HDL 胆固醇水平相关（P=4.15×10）。此外，我们观察到两个与红细胞性状相关的全基因组显著关联的位点，7q22.1 上的一个 13.2kb 的缺失（nssv15922542）和 12q24.12 上的一个 3.7kb 的缺失（nssv15813226），这两个缺失都位于先前报道与红细胞性状相关的区域。11q11 上的两个缺失（nssv15803200 和 nssv15802240），其中存在多个嗅觉受体基因簇，以及 DOCK5 上游的一个缺失（nssv15929560），与儿童肥胖相关。最后，当我们将具有亚阈值显著表型关联的拷贝数缺失（TADs）定义为 CNDs（P<10）时，我们在非编码区域中鉴定到了 157 个（97.5%）TADs，平均大小为 4kb（范围：209-47942bp）。
我们对 UK10K 全基因组测序队列进行了重新分析，鉴定到了多个与定量性状相关的高可信度拷贝数缺失。这些缺失具有标准的 dbVar ID，并复制了先前的发现，同时还揭示了需要进一步复制研究的新位点。
