@article {526,
	title = {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.},
	journal = {Hum Genet},
	volume = {137},
	year = {2018},
	month = {2018 Jul},
	pages = {553-567},
	abstract = {<p>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 {\textquoteright}induced{\textquoteright} 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 {\texttimes} 10 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.</p>},
	keywords = {Adolescent, Congenital Abnormalities, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genomics, Genotype, Haplotypes, Humans, Phenotype, Polymorphism, Single Nucleotide, Scoliosis},
	issn = {1432-1203},
	doi = {10.1007/s00439-018-1910-3},
	author = {Liu, Jiaqi and Zhou, Yangzhong and Liu, Sen and Song, Xiaofei and Yang, Xin-Zhuang and Fan, Yanhui and Chen, Weisheng and Akdemir, Zeynep Coban and Yan, Zihui and Zuo, Yuzhi and Du, Renqian and Liu, Zhenlei and Yuan, Bo and Zhao, Sen and Liu, Gang and Chen, Yixin and Zhao, Yanxue and Lin, Mao and Zhu, Qiankun and Niu, Yuchen and Liu, Pengfei and Ikegawa, Shiro and Song, You-Qiang and Posey, Jennifer E and Qiu, Guixing and Zhang, Feng and Wu, Zhihong and Lupski, James R and Wu, Nan}
}
@article {107,
	title = {Comparative Genomic Analyses of the Human NPHP1 Locus Reveal Complex Genomic Architecture and Its Regional Evolution in Primates.},
	journal = {PLoS Genet},
	volume = {11},
	year = {2015},
	month = {2015 Dec},
	pages = {e1005686},
	abstract = {<p>Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM$\#$ 256100) is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs) are abundant. Loss of function of NPHP1 is responsible for approximately 85\% of the NPHP1 cases-about 80\% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via nonallelic homologous recombination (NAHR) between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV) haplotypes at the NPHP1 locus that may protect a haploid genome from the NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans suggest that intra-species polymorphism may potentially modulate an individual{\textquoteright}s susceptibility to acquiring disease-associated alleles. </p>},
	keywords = {Adaptor Proteins, Signal Transducing, Alleles, Animals, Comparative Genomic Hybridization, Evolution, Molecular, Gene Dosage, Gene Rearrangement, Genome, Human, Genomic Structural Variation, Haplotypes, Humans, Kidney Diseases, Cystic, Membrane Proteins, Primates},
	issn = {1553-7404},
	doi = {10.1371/journal.pgen.1005686},
	author = {Yuan, Bo and Liu, Pengfei and Gupta, Aditya and Beck, Christine R and Tejomurtula, Anusha and Campbell, Ian M and Gambin, Tomasz and Simmons, Alexandra D and Withers, Marjorie A and Harris, R Alan and Rogers, Jeffrey and Schwartz, David C and Lupski, James R}
}
