A Method to Assess Linkage Disequilibrium between CNVs and SNPs Inside Copy Number Variable Regions

Since the discovery of the ubiquitous contribution of copy number variation to genetic variability, researchers have commonly used metrics such as r2 to quantify linkage disequilibrium (LD) between copy number variants (CNVs) and single nucleotide polymorphisms (SNPs). However, these reports have been restricted to SNPs outside copy number variable regions (CNVR) as current methods have not been adapted to account for SNPs displaying variable copy number. We show that traditional LD metrics inappropriately quantify SNP/CNV covariance when SNPs lie within CNVR. We derive a new method for measuring LD that solves this issue, and defaults to traditional metrics otherwise. Finally, we present a procedure to estimate CNV–SNP allele frequencies from unphased CNV–SNP genotypes. Our method allows researchers to include all SNPs in SNP/CNV LD measurements, regardless of copy number

A Highly Polymorphic Copy Number Variant in the NSF Gene is Associated with Cocaine Dependence

Cocaine dependence is a complex psychiatric disorder involving both genetic and environmental factors. Several neurotransmitter systems mediate cocaine's effects, dependence and relapse, being the components of the neurotransmitter release machinery good candidates for the disorder. Previously, we identified a risk haplotype for cocaine dependence in the NSF gene, encoding the protein N-Ethylmaleimide-Sensitive Factor essential for synaptic vesicle turnover. Here we examined the possible contribution to cocaine dependence of a large copy number variant (CNV) that encompasses part of the NSF gene. We performed a case-control association study in a discovery sample (359 cases and 356 controls) and identified an association between cocaine dependence and the CNV (P=0.013), that was confirmed in the replication sample (508 cases and 569 controls, P=7.1e-03) and in a pooled analysis (P=1.8e-04), with an over-representation of low number of copies in cases. Subsequently, we studied the functional impact of the CNV on gene expression and found thatthe levels of two NSF transcripts were significantly increased in peripheral blood mononuclear cells (PBMC) along with the number of copies of the CNV. These results, together with a previous study from our group, support the role of NSF in the susceptibility to cocaine dependenc

The Impact of Errors in Copy Number Variation Detection Algorithms on Association Results

The inaccuracy of copy number variation (CNV) detection on single nucleotide polymorphism (SNP) arrays has recently been brought to attention. Such high error rates will undoubtedly have ramifications on downstream association testing. We examined this effect for a wide range of scenarios and found a noticeable decrease in power for error rates typical of CNV calling algorithms. We compared power using CNV calls to the log relative ratio and found the latter to be superior when error rates are moderate to large or when the CNV size is small. It is our recommendation that CNV researchers use intensity measurements as an alternative to CNV calls in these scenarios

Common susceptibility variants are shared between schizophrenia and psoriasis in the Han Chinese population

Previous studies have shown that individuals with schizophrenia have a greater risk for psoriasis than a typical person. This suggests that there might be a shared genetic etiology between the 2 conditions. We aimed to characterize the potential shared genetic susceptibility between schizophrenia and psoriasis using genome-wide marker genotype data

Copy Number Variations Associated With Obesity‐Related Traits in African Americans: A Joint Analysis Between GENOA and HyperGEN

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95398/1/oby.2012.162.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/95398/2/oby_2790_sm_oby2012162_coi.pd

Chip-based direct genotyping of coding variants in genome wide association studies: Utility, issues and prospects

There is considerable debate about the most efficient way to interrogate rare coding variants in association studies. The options include direct genotyping of specific known coding variants in genes or, alternatively, sequencing across the entire exome to capture known as well as novel variants. Each strategy has advantages and disadvantages, but the availability of cost-efficient exome arrays has made the former appealing. Here we consider the utility of a direct genotyping chip, the Illumina HumanExome array (HE), by evaluating its content based on: 1. functionality; and 2. amenability to imputation. We explored these issues by genotyping a large, ethnically diverse cohort on the HumanOmniExpressExome array (HOEE) which combines the HE with content from the GWAS array (HOE). We find that the use of the HE is likely to be a cost-effective way of expanding GWAS, but does have some drawbacks that deserve consideration when planning studies

Genome-wide joint SNP and CNV analysis of aortic root diameter in African Americans: the HyperGEN study

<p>Abstract</p> <p>Background</p> <p>Aortic root diameter is a clinically relevant trait due to its known relationship with the pathogenesis of aortic regurgitation and risk for aortic dissection. African Americans are an understudied population despite a particularly high burden of cardiovascular diseases. We report a genome-wide association study on aortic root diameter among African Americans enrolled in the HyperGEN study. We invoked a two-stage, mixed model procedure to jointly identify SNP allele and copy number variation effects.</p> <p>Results</p> <p>Results suggest novel genetic contributors along a large region between the <it>CRCP </it>and <it>KCTD7 </it>genes on chromosome 7 (p = 4.26 × 10^<b>-7</b>); and the <it>SIRPA </it>and <it>PDYN </it>genes on chromosome 20 (p = 3.28 × 10^<b>-8</b>).</p> <p>Conclusions</p> <p>The regions we discovered are candidates for future studies on cardiovascular outcomes, particularly in African Americans. The methods we employed can also provide an outline for genetic researchers interested in jointly testing SNP and CNV effects and/or applying mixed model procedures on a genome-wide scale.</p

Common susceptibility variants are shared between schizophrenia and psoriasis in the Han Chinese population

Background Previous studies have shown that individuals with schizophrenia have a greater risk for psoriasis than a typical person. This suggests that there might be a shared genetic etiology between the 2 conditions. We aimed to characterize the potential shared genetic susceptibility between schizophrenia and psoriasis using genome-wide marker genotype data. Methods We obtained genetic data on individuals with psoriasis, schizophrenia and control individuals. We applied a marker-based coheritability estimation procedure, polygenic score analysis, a gene set enrichment test and a least absolute shrinkage and selection operator regression model to estimate the potential shared genetic etiology between the 2 diseases. We validated the results in independent schizophrenia and psoriasis cohorts from Singapore. Results We included 1139 individuals with psoriasis, 744 with schizophrenia and 1678 controls in our analysis, and we validated the results in independent cohorts, including 441 individuals with psoriasis (and 2420 controls) and 1630 with schizophrenia (and 1860 controls). We estimated that a large fraction of schizophrenia and psoriasis risk could be attributed to common variants (h(SNP)(2) = 29% 5.0%, p = 2.00 x 10(-8)), with a coheritability estimate between the traits of 21%. We identified 5 variants within the human leukocyte antigen (HLA) gene region, which were most likely to be associated with both diseases and collectively conferred a significant risk effect (odds ratio of highest risk quartile = 6.03, p &lt; 2.00 x 10(-16)). We discovered that variants contributing most to the shared heritable component between psoriasis and schizophrenia were enriched in antigen processing and cell endoplasmic reticulum. Limitations Our sample size was relatively small. The findings of 5 HLA gene variants were complicated by the complex structure in the HLA region. Conclusion We found evidence for a shared genetic etiology between schizophrenia and psoriasis. The mechanism for this shared genetic basis likely involves immune and calcium signalling pathways.National Natural Science Foundation of China [81370044, 81000692, 81273301, 81072461, 81130031, 81222022, 81222017]; China Council of Scholarship [201208340003]; Youth Project of the Outstanding Talents of Organization Department of the CPC Central Committee Program [31200939]; Pre-National Basic Research Program of China (973 Plan) [2012CB722404]; Anhui Province Natural Science Foundation [1208085QH145]; Anhui High Education Young Talent; Anhui Medical University [XJ201429]; NIH [1UL1TR001114, U19 AG023122-09, R01 DA030976-05, R01 MH094483-03, R01 AG035020-05, R01 MH100351-02, R21 AG045789-01A1]; Human Longevity, Inc.; Johnson and Johnson; Tanner Foundation; Stand-Up-to-Cancer organization; National Research Foundation Singapore under the National Medical Research Council Translational and Clinical Research Flagship Program [NMRC/TCR/003/2008]SCI(E)[email protected]; [email protected]

Genome-Wide Detection of Allele Specific Copy Number Variation Associated with Insulin Resistance in African Americans from the HyperGEN Study

African Americans have been understudied in genome wide association studies of diabetes and related traits. In the current study, we examined the joint association of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with fasting insulin and an index of insulin resistance (HOMA-IR) in the HyperGEN study, a family based study with proband ascertainment for hypertension. This analysis is restricted to 1,040 African Americans without diabetes. We generated allele specific CNV genotypes at 872,243 autosomal loci using Birdsuite, a freely available multi-stage program. Joint tests of association for SNPs and CNVs were performed using linear mixed models adjusting for covariates and familial relationships. Our results highlight SNPs associated with fasting insulin and HOMA-IR (rs6576507 and rs8026527, 3.7*10−7≤P≤1.1*10−5) near ATPase, class V, type 10A (ATP10A), and the L Type voltage dependent calcium channel (CACNA1D, rs1401492, P≤5.2*10−6). ATP10A belongs to a family of aminophospholipid-transporting ATPases and has been associated with type 2 diabetes in mice. CACNA1D has been linked to pancreatic beta cell generation in mice. The two most significant copy variable markers (rs10277702 and rs361367; P<2.0*10−4) were in the beta variable region of the T-cell receptor gene (TCRVB). Human and mouse TCR has been shown to mimic insulin and its receptor and could contribute to insulin resistance. Our findings differ from genome wide association studies of fasting insulin and other diabetes related traits in European populations, highlighting the continued need to investigate unique genetic influences for understudied populations such as African Americans

Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis

Correction: vol 7, 13205, 2016, doi:10.1038/ncomms13205Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in Bone-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h(2) = 0.18, P value = 0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.Peer reviewe