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Hum Genet. 2018 Jul;137(6-7):553-567. doi: 10.1007/s00439-018-1910-3. Epub 2018 Jul 17.

The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease.

Liu J1,2,3, Zhou Y2,4, Liu S1,2,5, Song X6, Yang XZ7, Fan Y8, Chen W1,2,5, Akdemir ZC6, Yan Z1,2,5, Zuo Y1,2,5, Du R6, Liu Z2,9, Yuan B6, Zhao S1,2,5, Liu G1,2,5, Chen Y1,2,5, Zhao Y1,2,5, Lin M1,2,5, Zhu Q1,2,5, Niu Y2,5,7, Liu P6, Ikegawa S10, Song YQ8, Posey JE6, Qiu G1,2,5; DISCO (Deciphering disorders Involving Scoliosis and COmorbidities) Study, Zhang F11,12, Wu Z2,5,7, Lupski JR6,13,14, Wu N15,16,17.

Author information

1
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China.
2
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China.
3
Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
4
Department of Internal Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.
5
Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
7
Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.
8
School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.
9
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
10
Laboratory of Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, 108-8639, Japan.
11
Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, 200433, China.
12
Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200433, China.
13
Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
14
Texas Children's Hospital, Houston, TX, 77030, USA.
15
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Beijing, 100730, China. dr.wunan@pumch.cn.
16
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100730, China. dr.wunan@pumch.cn.
17
Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, 100730, China. dr.wunan@pumch.cn.

Abstract

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be 'induced' by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p < 1 × 10-6 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.

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