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

Human Genetics
Jiaqi LiuNan Wu

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 ...Continue Reading

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Citations

Mar 8, 2020·Pharmacological Reviews·Melanie A FelmleeMarilyn E Morris
Jan 24, 2020·Chinese Medical Journal·Yue PengQian-Yu Zhuang
Jun 20, 2020·ELife·Marie PereiraJacques Behmoaras
Nov 2, 2019·Mitochondrion·Balaji RamkumarAmere Subbarao Sreedhar
Apr 16, 2021·BMC Genomics·Maria K RosengrenGabriella Lindgren
Apr 23, 2021·Journal of the Chinese Medical Association : JCMA·Zhi-Xiong ChongHan-Kiat Ong
Oct 16, 2020·Orphanet Journal of Rare Diseases·Wen TianUNKNOWN (Deciphering Disorders Involving Scoliosis, COmorbidities) study group
Jul 21, 2021·Biochemical Society Transactions·Ali AfrasiabiHamid Alinejad-Rokny

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Methods Mentioned

BETA
genotyping
PCR

Software Mentioned

SPSS
Illumina
PLINK
PennCNV
QuantiSNP
circos
Genotyping Console
Affymetrix
Haploview
SNPstats

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