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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Abbreviations
- CNV:
-
Copy number variation
- SNV:
-
Single nucleotide variant
- SNP:
-
Single nucleotide polymorphism
- DISCO study:
-
Deciphering Disorders Involving Scoliosis and Comorbidities study
- GWAS:
-
Genome-wide association studies
- CS:
-
Congenital scoliosis
- NGS:
-
Next-generation sequencing
- qPCR:
-
Quantitative polymerase chain reaction
- aCGH:
-
Array-based comparative genomic hybridization microarray
- MLPA:
-
Multiplex ligation-dependent probe amplification
- HWE:
-
Hardy–Weinberg equilibrium
- AF:
-
Allele frequency
- CGR:
-
Complex genomic rearrangements
- CMT1A-REPs:
-
Charcot–Marie–Tooth disease type 1A-repeats
- ExAC:
-
Exome Aggregation Consortium
- NHGRI:
-
National Human Genome Research Institute
- DGV:
-
Database of Genomic Variants
- PSV:
-
Paralogous sequence variant
- OR:
-
Odds ratio
- CI:
-
Confidence interval
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Acknowledgements
We would like to thank all the individuals involved in the study for their participation.
Funding
This research was funded in part by the National Natural Science Foundation of China (81501852 to N.W., 81472046 and 81772299 to Z.W., 81472045 and 81772301 to G.Q), Beijing Natural Science Foundation (7172175 to N.W.), Beijing Nova Program (Z161100004916123 to N.W.,), Beijing Nova Program Interdisciplinary Collaborative Project (xxjc201717 to N.W.), 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine (to N.W.), The Central Level Public Interest Program for Scientific Research Institute (2016ZX310177 to N.W.), PUMC Youth Fund and the Fundamental Research Funds for the Central Universities (3332016006 to N.W.), CAMS Initiative Fund for Medical Sciences (2016-I2M-3-003 to G.Q. and N.W., 2016-I2M-2-006 and 2017-I2M-2-001 to Z.W.), the Distinguished Youth Foundation of Peking Union Medical College Hospital (JQ201506 to N.W.), the 2016 PUMCH Science Fund for Junior Faculty (PUMCH-2016-1.1 to N.W.), the US National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS R01NS058529 and R35NS105078 to J.R.L), National Human Genome Research Institute/National Heart, Lung, and Blood Institute (NHGRI/NHLBI UM1 HG006542 to J.R.L), the National Human Genome Research Institute (NHGRI K08 HG008986 to J.E.P).
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J.R.L. has stock ownership in 23andMe and Lasergen, is a paid consultant for Regeneron Pharmaceuticals, and is a coinventor on multiple the United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Baylor Genetics Laboratory (http://bmgl.com).
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439_2018_1910_MOESM1_ESM.xlsx
Table S1. The significant SNPs related to clinical conditions in the National Human Genome Research Institute (NHGRI) Catalog of Published GWAS (XLSX 561 KB)
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Table S3. The total of 27,096 SNPs with significant difference between 196 AIS cases and 303 control subjects in the AIS genome-wide association study (XLSX 1651 KB)
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Table S4. The overlapping CNVs and disease-associated SNPs in the same region either in the AIS patients or controls in the genome-wide association study (XLSX 197 KB)
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Liu, J., Zhou, Y., Liu, S. et al. 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. Hum Genet 137, 553–567 (2018). https://doi.org/10.1007/s00439-018-1910-3
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DOI: https://doi.org/10.1007/s00439-018-1910-3