The individual and global impact of copy-number variants on complex human traits.
The individual and global impact of copy-number variants on complex human traits.
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DOI：
10.1016/j.ajhg.2022.02.010
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发表时间：
2022-04-07
影响因子：
9.8
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中科院分区：
文献类型：
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拷贝数变异（CNVs）对复杂人类特征的影响仍然研究不足。我们在331，522名英国生物库参与者中调用CNV，并在CNV代理探针的拷贝数和57个连续性状之间进行全基因组关联研究（GWAS），揭示了跨越47种表型的131个信号。我们的分析概括了众所周知的关联（例如，1 q21和身高），揭示了复发CNV的多效性（例如，16 p11.2-BP 4-BP 5和22 q11.21分别有26和16个性状），并提出了基因功能（例如，MARF 1在女性生殖中的作用）。48个CNV信号（38%）与单核苷酸多态性（SNP）-GWASs信号重叠。例如，编码尿酸盐转运蛋白支架蛋白的PDZK 1的缺失降低了血清尿酸盐水平，而编码恒河猴D血型抗原的RHD的缺失与血液学性状相关。其他信号与孟德尔紊乱区域重叠，表明这些基因座的可变表达性和广泛影响，如定位到转子综合征（SLCO 1B 1/3）、肾囊肿和糖尿病综合征（HNF 1B）或腓骨肌萎缩症（PMP 22）基因座的信号所示。总CNV负担对35个性状产生负面影响，导致肥胖增加，肝/肾损伤，智力和体能下降。在校正CNV-GWAS信号后，30个性状仍然与负担相关，表明多基因CNV结构。这种负担与社会经济指标、父母寿命和年龄（生存率代理）呈负相关，表明这是导致寿命缩短的原因。总之，我们的结果展示了研究CNVs如何扩大生物学见解，强调这种突变类在塑造人类特征方面的关键作用，并支持孟德尔和复杂疾病之间的连续性。
The impact of copy-number variations (CNVs) on complex human traits remains understudied. We called CNVs in 331,522 UK Biobank participants and performed genome-wide association studies (GWASs) between the copy number of CNV-proxy probes and 57 continuous traits, revealing 131 signals spanning 47 phenotypes. Our analysis recapitulated well-known associations (e.g., 1q21 and height), revealed the pleiotropy of recurrent CNVs (e.g., 26 and 16 traits for 16p11.2-BP4-BP5 and 22q11.21, respectively), and suggested gene functionalities (e.g., MARF1 in female reproduction). Forty-eight CNV signals (38%) overlapped with single-nucleotide polymorphism (SNP)-GWASs signals for the same trait. For instance, deletion of PDZK1, which encodes a urate transporter scaffold protein, decreased serum urate levels, while deletion of RHD, which encodes the Rhesus blood group D antigen, associated with hematological traits. Other signals overlapped Mendelian disorder regions, suggesting variable expressivity and broad impact of these loci, as illustrated by signals mapping to Rotor syndrome (SLCO1B1/3), renal cysts and diabetes syndrome (HNF1B), or Charcot-Marie-Tooth (PMP22) loci. Total CNV burden negatively impacted 35 traits, leading to increased adiposity, liver/kidney damage, and decreased intelligence and physical capacity. Thirty traits remained burden associated after correcting for CNV-GWAS signals, pointing to a polygenic CNV architecture. The burden negatively correlated with socio-economic indicators, parental lifespan, and age (survivorship proxy), suggesting a contribution to decreased longevity. Together, our results showcase how studying CNVs can expand biological insights, emphasizing the critical role of this mutational class in shaping human traits and arguing in favor of a continuum between Mendelian and complex diseases.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
8.9
作者：
Bielinski, Suzette J.;Chai, High Seng;Chute, Christopher G.
通讯作者：
Chute, Christopher G.
影响因子：
64.5
作者：
Astle, William J.;Elding, Heather;Soranzo, Nicole
通讯作者：
Soranzo, Nicole