High-resolution arrays reveal burden of copy number variations on Parkinson disease genes associated with increased disease risk in random cohorts

<p>Background: Parkinson disease (PD) is a neurological disease responsible for a considerable rate of mortality and morbidity in the society. Since the symptoms of the disease appear much later than the actual onset of neuron degeneration, a majority of cases remain undiagnosed until the manifestation of the symptoms.</p> <p>Objectives: In order to investigate the existence of such susceptibility in the population, we analyzed Copy Number Variation (CNV) influences on PD genes in 1715 individuals from 12 different populations.</p> <p>Results: Overall, 16 CNV-PD genes, 3 known to be causal and 13 associated, were found to be significantly enriched. PARK2, was under heavy burden with ~1% of the population containing CNV in the exonic region. The impact of these genes on the genome and disease pathway was analyzed using several genome analysis tools. Protein interaction network of CNV-PD genes revealed a complex interaction of molecules forming a major hub by the α-Synuclein, whose direct interactors, LRRK2, PARK2 and ATP13A2 are under CNV influence.</p> <p>Conclusions: We hypothesize that CNVs may not be the initiating event in the pathogenesis of PD and remain latent until additional secondary hits are acquired and also propose novel genes that may fall under the PD pathway which contribute in pathogenesis.</p

Functional and disease association annotation of the miRNA genes under the CNV burden.

<p>Functional and disease association annotation of the miRNA genes under the CNV burden.</p

Distribution of miRNA CNVs and genes across 12 populations.

<p>a) Represents distribution of miRNA and non-miRNA CNV types b) represents burden of miRNA genes under duplication and deletion CNVs; c) represents mean duplication and deletion CNV size; d) represents the percent distribution of singleton miRNA gene.</p

Population-wise and global frequency of recurrent miRNA-CNVs shared across 12 populations.

<p>Population-wise and global frequency of recurrent miRNA-CNVs shared across 12 populations.</p

Map of miRNA genes in different chromosomes across populations.

<p>Each color coded vertical line represents a single population.</p

Distribution of miRNA CNVs and genes across 12 populations.

<p>Distribution of miRNA CNVs and genes across 12 populations.</p

Copy Number State and Sex bias in miRNA sub-genome.

<p>a) Distribution of copy number states of the miRNA CNVs across 12 populations; b) represents the mean CN state across populations and c) represents the male-female distribution of miRNA genes under CNVs.</p

CNV miRNA pathway showing the CNV burden of miRNA genes and its interaction with target proteins indicating the involvement in biological functions and diseases.

<p>CNV miRNA pathway showing the CNV burden of miRNA genes and its interaction with target proteins indicating the involvement in biological functions and diseases.</p