CNV Analysis Associates AKNAD1 with Type-2 Diabetes in Jordan Subpopulations.

Christopher J Cardinale,Xiao Chang,Nancy Hakooz,Amina Sheshani,Rana Dajani,Jin Li,Zhi Wei,Joseph T Glessner,Yousef Khader,Hakon Hakonarson,Renata Pellegrino,Tiancheng Wang,Duaa Zandaki

doi:10.1038/srep13391

Abstract

Previous studies have identified a number of single nucleotide polymorphisms (SNPs) associated with type-2 diabetes (T2D), but copy number variation (CNV) association has rarely been addressed, especially in populations from Jordan. To investigate CNV associations for T2D in populations in Jordan, we conducted a CNV analysis based on intensity data from genome-wide SNP array, including 34 T2D cases and 110 healthy controls of Chechen ethnicity, as well as 34 T2D cases and 106 healthy controls of Circassian ethnicity. We found a CNV region in protein tyrosine phosphatase receptor type D (PTPRD) with significant association with T2D. PTPRD has been reported to be associated with T2D in genome-wide association studies (GWAS). We additionally identified 16 CNV regions associated with T2D which overlapped with gene exons. Of particular interest, a CNV region in the gene AKNA Domain Containing 1 (AKNAD1) surpassed the experiment-wide significance threshold. Endoplasmic reticulum (ER)-related pathways were significantly enriched among genes which are predicted to be functionally associated with human or mouse homologues of AKNAD1. This is the first CNV analysis of a complex disease in populations of Jordan. We identified and experimentally validated a significant CNVR in gene AKNAD1 associated with T2D.

Highlights

Copy number variants (CNVs) account for a major proportion of human genetic variation and have been expected to complement single nucleotide polymorphism (SNP) in implicating genetic susceptibility loci for common diseases
We investigated the potential role of rare variants in type 2 diabetes (T2D), by performing CNV analysis on two ethnic populations of ancient descent, the Circassians and the Chechens, which were genotyped by Illumina single nucleotide polymorphism (SNP) arrays
After quality control (QC) of genotyping data, 208 samples were retained in the analysis

Summary

Introduction

Copy number variants (CNVs) account for a major proportion of human genetic variation and have been expected to complement SNPs in implicating genetic susceptibility loci for common diseases. We investigated the potential role of rare variants in T2D, by performing CNV analysis on two ethnic populations of ancient descent, the Circassians and the Chechens, which were genotyped by Illumina single nucleotide polymorphism (SNP) arrays. A large diaspora of Circassians were relocated to Jordan and other regions of the Ottoman Empire as a result of war with the Russian Empire in 186416. These immigrants choose to be endogamous and have kept a distinct sense of identity and ethnicity during their last one hundred and fifty years of residence in Jordan[17]. The epidemiology of diabetes in the Circassian and Chechen communities in Jordan has been studied, showing a prevalence of impaired fasting glycemic control to be 18.5% for Circassians and 14.6% for Chechens while the prevalence of diabetes was reported to be 9.6% for Circassians and 10.1% for Chechens[18]

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