Faculty Bibliography
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219
Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies
BACKGROUND:In addition to HLA genetic incompatibility, non-HLA difference between donor and recipients of transplantation leading to allograft rejection are now becoming evident. We aimed to create a unique genome-wide platform to facilitate genomic research studies in transplant-related studies. We designed a genome-wide genotyping tool based on the most recent human genomic reference datasets, and included customization for known and potentially relevant metabolic and pharmacological loci relevant to transplantation. METHODS:We describe here the design and implementation of a customized genome-wide genotyping array, the 'TxArray', comprising approximately 782,000 markers with tailored content for deeper capture of variants across HLA, KIR, pharmacogenomic, and metabolic loci important in transplantation. To test concordance and genotyping quality, we genotyped 85 HapMap samples on the array, including eight trios. RESULTS:We show low Mendelian error rates and high concordance rates for HapMap samples (average parent-parent-child heritability of 0.997, and concordance of 0.996). We performed genotype imputation across autosomal regions, masking directly genotyped SNPs to assess imputation accuracy and report an accuracy of >0.962 for directly genotyped SNPs. We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms. Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms. CONCLUSIONS:We have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies.
PMCID:4589899
PMID: 26423053
ISSN: 1756-994x
CID: 5478362
Copy number variation in CEP57L1 predisposes to congenital absence of bilateral ACL and PCL ligaments
BACKGROUND:Absence of the anterior (ACL) or posterior cruciate ligament (PCL) are rare congenital malformations that result in knee joint instability, with a prevalence of 1.7 per 100,000 live births and can be associated with other lower-limb abnormalities such as ACL agnesia and absence of the menisci of the knee. While a few cases of absence of ACL/PCL are reported in the literature, a number of large familial case series of related conditions such as ACL agnesia suggest a potential underlying monogenic etiology. We performed whole exome sequencing of a family with two individuals affected by ACL/PCL. RESULTS:We identified copy number variation (CNV) deletion impacting the exon sequences of CEP57L1, present in the affected mother and her affected daughter based on the exome sequencing data. The deletion was validated using quantitative PCR (qPCR), and the gene was confirmed to be expressed in ACL ligament tissue. Interestingly, we detected reduced expression of CEP57L1 in Epstein-Barr virus (EBV) cells from the two patients in comparison with healthy controls. Evaluation of 3D protein structure showed that the helix-binding sites of the protein remain intact with the deletion, but other functional binding sites related to microtubule attachment are missing. The specificity of the CNV deletion was confirmed by showing that it was absent in ~700 exome sequencing samples as well as in the database of genomic variations (DGV), a database containing large numbers of annotated CNVs from previous scientific reports. CONCLUSIONS:We identified a novel CNV deletion that was inherited through an autosomal dominant transmission from an affected mother to her affected daughter, both of whom suffered from the absence of the anterior and posterior cruciate ligaments of the knees.
PMID: 26561035
ISSN: 1479-7364
CID: 5478372
Identifying gene-gene interactions that are highly associated with Body Mass Index using Quantitative Multifactor Dimensionality Reduction (QMDR)
BACKGROUND:Despite heritability estimates of 40-70 % for obesity, less than 2 % of its variation is explained by Body Mass Index (BMI) associated loci that have been identified so far. Epistasis, or gene-gene interactions are a plausible source to explain portions of the missing heritability of BMI. METHODS:Using genotypic data from 18,686 individuals across five study cohorts - ARIC, CARDIA, FHS, CHS, MESA - we filtered SNPs (Single Nucleotide Polymorphisms) using two parallel approaches. SNPs were filtered either on the strength of their main effects of association with BMI, or on the number of knowledge sources supporting a specific SNP-SNP interaction in the context of BMI. Filtered SNPs were specifically analyzed for interactions that are highly associated with BMI using QMDR (Quantitative Multifactor Dimensionality Reduction). QMDR is a nonparametric, genetic model-free method that detects non-linear interactions associated with a quantitative trait. RESULTS:We identified seven novel, epistatic models with a Bonferroni corrected p-value of association < 0.1. Prior experimental evidence helps explain the plausible biological interactions highlighted within our results and their relationship with obesity. We identified interactions between genes involved in mitochondrial dysfunction (POLG2), cholesterol metabolism (SOAT2), lipid metabolism (CYP11B2), cell adhesion (EZR), cell proliferation (MAP2K5), and insulin resistance (IGF1R). Moreover, we found an 8.8 % increase in the variance in BMI explained by these seven SNP-SNP interactions, beyond what is explained by the main effects of an index FTO SNP and the SNPs within these interactions. We also replicated one of these interactions and 58 proxy SNP-SNP models representing it in an independent dataset from the eMERGE study. CONCLUSION/CONCLUSIONS:This study highlights a novel approach for discovering gene-gene interactions by combining methods such as QMDR with traditional statistics.
PMCID:4678717
PMID: 26674805
ISSN: 1756-0381
CID: 5478382
Elevated Fibroblast Growth Factor 23 Concentration: Prediction of Mortality among Chronic Kidney Disease Patients
BACKGROUND:The osteocyte-derived hormone, fibroblast growth factor 23 (FGF23), regulates the phosphorus metabolism and suppresses 1,25-dihydroxyvitamin D production, thereby mitigating hyperphosphatemia in patients with renal disorders. An elevated FGF23 level is suggested to be an early biomarker of altered phosphorus metabolism in the initial stages of chronic kidney disease (CKD) and acts as a strong predictor of mortality in dialysis patients. In the Saudi population, there is no report on the FGF23 level in CKD patients to date. This study aims to estimate the plasma FGF23 levels in the Saudi population and to correlate it with its clinical manifestations in order to ascertain its role in the pathogenesis of CKD patients. METHODS:The FGF23 level in the plasma samples was determined using ELISA in a diverse cohort of 89 cases with stage 3-5 CKD and 100 healthy subjects. The plasma FGF23 level was correlated with other biochemical parameters. RESULTS:The results revealed that the FGF23 level was markedly elevated among CKD patients compared to the control group, and a significant inverse correlation was observed between the FGF23 level and glomerular filtration rate. FGF23 elevation was approximately 40-fold among stage 5 patients compared to the control, while the elevation of phosphate, parathyroid hormone (PTH) and alkaline phosphatase was 2-, 3- and 8-fold in this stage, respectively. CONCLUSION/CONCLUSIONS:Elevated FGF23 levels may have a strong correlation with the disease pathogenesis. In addition, FGF23 might be a future therapeutic target to intervene against the progression of CKD as well as to increase patient survivability.
PMCID:4698654
PMID: 27194998
ISSN: 1664-3828
CID: 5478462
Risk of Preeclampsia in Patients With Genetic Predisposition To Common Medical Conditions [Meeting Abstract]
ISI:000351407202053
ISSN: 1933-7191
CID: 5479102
SESSION INTRODUCTION: CHARACTERIZING THE IMPORTANCE OF ENVIRONMENTAL EXPOSURES, INTERACTIONS BETWEEN THE ENVIRONMENT AND GENETIC ARCHTECTURE, AND GENETC INTERACTIONS: NEW METHODS FOR UNDERSTANDING THE ETIOLOGY OF COMPLEX TRAITS AND DISEASE [Meeting Abstract]
ISI:000461835500016
ISSN: 2335-6936
CID: 5479162
Genetic sharing and heritability of paediatric age of onset autoimmune diseases
Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863+/-s.e. 0.07) and JIA (0.727+/-s.e. 0.037), more modest for UC (0.386+/-s.e. 0.04) and CD (0.454+/-0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69+/-s.e. 0.07) and JIA-CVID (0.343+/-s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.
PMCID:4633631
PMID: 26450413
ISSN: 2041-1723
CID: 1808672
Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases
Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse chi(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.
PMCID:4863040
PMID: 26301688
ISSN: 1546-170x
CID: 1809002
Transplantation genetics: current status and prospects
Over the last decade, advances in genetic technologies have accelerated our understanding of the genetic diversity across individuals and populations. Case-control and population-based studies have led to several thousand genetic associations across a range of phenotypes and traits being unveiled. Despite widespread and successful use of organ transplantation as a curative therapy for organ failure, genetic research has yet to make a major impact on transplantation practice aside from HLA matching. New studies indicate that non-HLA loci, termed minor histocompatibility antigens (mHAs), may play an important role in graft rejection. With several million common and rare polymorphisms observed between any two unrelated individuals, a number of these polymorphisms represent mHAs, and may underpin transplantation rejection. Genetic variation is also recognized as contributing to clinical outcomes including response to immunosuppressants, introducing the possibility of genotype-guided prescribing in the very near future. This review summarizes existing knowledge of the impact of genetics on transplantation outcomes and therapeutic responses, and highlights the translational potential that new genomic knowledge may bring to this field.
PMID: 24618335
ISSN: 1600-6143
CID: 5479342
Return of genomic results to research participants: the floor, the ceiling, and the choices in between
As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants' health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles.
PMCID:4121476
PMID: 24814192
ISSN: 1537-6605
CID: 5479422
