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.

TitleThe 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.
Publication TypeJournal Article
Year of Publication2018
AuthorsLiu, J, Zhou, Y, Liu, S, Song, X, Yang, X-Z, Fan, Y, Chen, W, Akdemir, ZCoban, Yan, Z, Zuo, Y, Du, R, Liu, Z, Yuan, B, Zhao, S, Liu, G, Chen, Y, Zhao, Y, Lin, M, Zhu, Q, Niu, Y, Liu, P, Ikegawa, S, Song, Y-Q, Posey, JE, Qiu, G, Zhang, F, Wu, Z, Lupski, JR, Wu, N
Corporate AuthorsDISCO (Deciphering disorders Involving Scoliosis and COmorbidities) Study
JournalHum Genet
Volume137
Issue6-7
Pagination553-567
Date Published2018 Jul
ISSN1432-1203
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 

DOI10.1007/s00439-018-1910-3
Alternate JournalHum. Genet.
PubMed ID30019117
PubMed Central IDPMC6200315
Grant ListR35NS105078 / / National Institute of Neurological Disorders and Stroke /
81472045 / / National Natural Science Foundation of China /
2016-I2M-2-006 / / CAMS Initiative Fund for Medical Sciences /
NINDS R01NS058529 / / National Institute of Neurological Disorders and Stroke /
xxjc201717 / / Beijing Nova Program Interdisciplinary Collaborative Project /
81772301 / / National Natural Science Foundation of China /
3332016006 / / PUMC Youth Fund & the Fundamental Research Funds for the Central Universities /
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
2016ZX310177 / / The Central Level Public Interest Program for Scientific Research Institute /
K08 HG008986 / HG / NHGRI NIH HHS / United States
NHGRI/NHLBI UM1 HG006542 / / National Human Genome Research Institute /
Z161100004916123 / / Beijing Nova Program /
PUMCH-2016-1.1 / / the 2016 PUMCH Science Fund for Junior Faculty /
81472046 / / National Natural Science Foundation of China /
JQ201506 / / the Distinguished Youth Foundation of Peking Union Medical College Hospital /
81501852 / / National Natural Science Foundation of China /
R01 NS058529 / NS / NINDS NIH HHS / United States
NHGRI K08 HG008986 / / National Human Genome Research Institute /
2016-I2M-3-003 / / CAMS Initiative Fund for Medical Sciences /
81772299 / / National Natural Science Foundation of China /
2017-I2M-2-001 / / CAMS Initiative Fund for Medical Sciences /
7172175 / / Beijing Natural Science Foundation /