Andrew D Paterson

SickKids, Toronto, Ontario, Canada

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Publications (273)2048.06 Total impact

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    ABSTRACT: The risk of long-term diabetes complications is not fully explained by diabetes duration or long-term glycemic exposure, suggesting the involvement of genetic factor(s). Since thiamine regulates intracellular glucose metabolism and corrects for multiple damaging effects of high glucose, we hypothesised that variants in specific thiamine transporters are associated with risk of severe retinopathy and/or severe nephropathy, as they might modify an individual's ability to achieve sufficiently high intracellular thiamine levels. We tested 134 single-nucleotide polymorphisms (SNPs) in two thiamine transporters (SLC19A2/3) and their transcription factors (SP1/2) for association with severe retinopathy, nephropathy or their combination in the FinnDiane cohort. Subsequently, the results were examined for replication in the DCCT/EDIC and WESDR cohorts. We found two SNPs in strong linkage disequilibrium in the SLC19A3 locus associated with reduced rate of severe retinopathy and the combined phenotype of severe retinopathy and end-stage renal disease. The association for the combined phenotype reached genome-wide significance in a meta-analysis including the WESDR cohort. These findings suggest that genetic variations in SLC19A3 may play an important role in the pathogenesis of severe diabetic retinopathy and nephropathy. This may help explain why some persons with type 1 diabetes are less prone than others to develop microvascular complications.
    No preview · Article · Dec 2015 · Diabetes
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    ABSTRACT: Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and associate with increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes mellitus and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (p=2.4*10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. SNPs at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in average UACR per minor allele was 21% for HS6ST1 and 13% for RAB38/CTSC (p=6.3*10(-7) and 5.8*10(-7), respectively). Experiments using streptozotocin-treated diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout vs. control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared to controls. The loci identified here confirm known and highlight novel pathways influencing albuminuria.
    Full-text · Article · Dec 2015 · Diabetes
  • Marc R. Woodbury-Smith · Andrew D. Paterson · Hilary Coon

    No preview · Conference Paper · Nov 2015
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    ABSTRACT: Background: While family history provides important information on risk of developing Inflammatory Bowel Disease (IBD), genetic profiling of first degree relatives (FDR) of Crohn's Disease (CD) - affected individuals might provide additional information. We aimed to delineate the genetic contribution to the increased IBD susceptibility observed in FDR. Methods: N=976 Caucasian, healthy, non-related FDR; n=4997 independent CD and n=5000 healthy controls (HC); were studied. Genotyping for 158 IBD-associated single nucleotide polymorphisms (SNPs) was performed using the Illumina Immunochip. Risk allele frequency (RAF) differences between FDR and HC cohorts were correlated with those between CD and HC cohorts. CD and IBD genetic risk scores (GRS) were calculated and compared between HC, FDR and CD cohorts. Results: IBD-associated SNP RAF differences in FDR and HC cohorts were strongly correlated with those in CD and HC cohorts, correlation coefficient 0.63 [95%CI 0.53 - 0.72], p = 9.90 x 10(-19). There was a significant increase in CD-GRS (mean) comparing HC, FDR and CD cohorts: 0.0244, 0.0250 and 0.0257 respectively (p < 1 x 10(-7) for each comparison). There was no significant difference in the IBD-GRS between HC and FDR cohorts (p=0.81); however IBD-GRS was significantly higher in CD compared with FDR and HC cohorts (p < 10(-10) for each comparison). Conclusion: FDR of CD-affected individuals are enriched with IBD risk alleles compared with HC. Cumulative CD-specific genetic risk is increased in FDR compared with HC. Prospective studies are required to determine if genotyping would facilitate better risk stratification of FDR.
    No preview · Article · Oct 2015 · Journal of Crohn s and Colitis
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    ABSTRACT: Renal disease variability in autosomal dominant polycystic kidney disease (ADPKD) is strongly influenced by the gene locus (PKD1 versus PKD2). Recent studies identified nontruncating PKD1 mutations in approximately 30% of patients who underwent comprehensive mutation screening, but the clinical significance of these mutations is not well defined. We examined the genotype-renal function correlation in a prospective cohort of 220 unrelated ADPKD families ascertained through probands with serum creatinine ≤1.4 mg/dl at recruitment. We screened these families for PKD1 and PKD2 mutations and reviewed the clinical outcomes of the probands and affected family members. Height-adjusted total kidney volume (htTKV) was obtained in 161 affected subjects. Multivariate Cox proportional hazard modeling for renal and patient survival was performed in 707 affected probands and family members. Overall, we identified pathogenic mutations in 84.5% of our families, in which the prevalence of PKD1 truncating, PKD1 in-frame insertion/deletion, PKD1 nontruncating, and PKD2 mutations was 38.3%, 4.3%, 27.1%, and 30.3%, respectively. Compared with patients with PKD1 truncating mutations, patients with PKD1 in-frame insertion/deletion, PKD1 nontruncating, or PKD2 mutations have smaller htTKV and reduced risks (hazard ratio [95% confidence interval]) of ESRD (0.35 [0.14 to 0.91], 0.10 [0.05 to 0.18], and 0.03 [0.01 to 0.05], respectively) and death (0.31 [0.11 to 0.87], 0.20 [0.11 to 0.38], and 0.18 [0.11 to 0.31], respectively). Refined genotype-renal disease correlation coupled with targeted next generation sequencing of PKD1 and PKD2 may provide useful clinical prognostication for ADPKD.
    No preview · Article · Oct 2015 · Journal of the American Society of Nephrology
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    Preview · Dataset · Oct 2015
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    ABSTRACT: Objective: To determine whether distinct single nucleotide polymorphisms (SNPs) within the glutamate receptor ionotropic NMDA 1 gene (GRIN1) are associated with NMDA receptor (NMDAR) encephalitis and whether these same variants are associated with variability in the clinical presentation and course of affected patients. Methods: We performed clinical follow-up on 48 patients with NMDAR encephalitis and NMDAR autoantibodies detected in serum or CSF. All RefSeq GRIN1 coding exons were sequenced in 39 Caucasian-European patients, and the frequencies of SNPs were compared with those of an ethnically similar population using a case-control study design. Predetermined clinical variables were compared between patients with and without identified SNPs. Results: Two SNPs were identified in GRIN1: 24 (62%) Caucasian-European patients with NMDAR encephalitis had alternate alleles at both rs6293 (exon 6) and rs1126442 (exon 7; exon numbering according to NM_001185090). The SNPs were in complete linkage disequilibrium. The frequency of these variants did not differ between patients with NMDAR encephalitis and ethnically matched individuals in the general population. No differences in clinical presentation, measures of disease severity, clinical course, or outcomes were observed between patients with different genotypes at these SNPs. Conclusion: Disease susceptibility or course in patients with NMDAR encephalitis was not strongly affected by SNPs in GRIN1. This study provides an estimate of the frequency of SNPs in GRIN1 in patients with NMDAR encephalitis and emphasizes the need for multisite collaborative studies enrolling larger numbers of patients to identify the genetic contributions to NMDAR encephalitis.
    Full-text · Article · Sep 2015
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    ABSTRACT: The "winner's curse" is a subtle and difficult problem in interpretation of genetic association, in which association estimates from large-scale gene detection studies are larger in magnitude than those from subsequent replication studies. This is practically important because use of a biased estimate from the original study will yield an underestimate of sample size requirements for replication, leaving the investigators with an underpowered study. Motivated by investigation of the genetics of type 1 diabetes complications in a longitudinal cohort of participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Genetics Study, we apply a bootstrap resampling method in analysis of time to nephropathy under a Cox proportional hazards model, examining 1,213 single-nucleotide polymorphisms (SNPs) in 201 candidate genes custom genotyped in 1,361 white probands. Among 15 top-ranked SNPs, bias reduction in log hazard ratio estimates ranges from 43.1% to 80.5%. In simulation studies based on the observed DCCT/EDIC genotype data, genome-wide bootstrap estimates for false-positive SNPs and for true-positive SNPs with low-to-moderate power are closer to the true values than uncorrected naïve estimates, but tend to overcorrect SNPs with high power. This bias-reduction technique is generally applicable for complex trait studies including quantitative, binary, and time-to-event traits.
    Preview · Article · Sep 2015 · Genetic Epidemiology
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    ABSTRACT: A variant (rs1495741) in the gene for the N-acetyltransferase 2 (NAT2) protein is associated with skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation end products and other fluorophores in the skin. Because NAT2 is involved in caffeine metabolism, we aimed to determine whether caffeine consumption is associated with SIF and whether rs1495741 is associated with SIF independently of caffeine. SIF was measured in 1,181 participants with type 1 diabetes from the Epidemiology of Diabetes Interventions and Complications study. Two measures of SIF were used: SIF1, using a 375-nm excitation light-emitting diode (LED), and SIF14 (456-nm LED). Food frequency questionnaires were used to estimate mean caffeine intake. To establish replication, we examined a second type 1 diabetes cohort. Higher caffeine intake was significantly associated with higher SIF1LED 375 nm[0.6, 0.2] (P=2×10(-32)) and SIF14LED 456 nm[0.4, 0.8] (P=7×10(-31)) and accounted for 4% of the variance in each after adjusting for covariates. When analyzed together, caffeine intake and rs1495741 both remained highly significantly associated with SIF1LED 375 nm[0.6, 0.2] and SIF14LED 456 nm[0.4, 0.8]. Mean caffeinated coffee intake was also positively associated with SIF1LED 375 nm[0.6, 0.2] (P=9×10(-12)) and SIF14LED 456 nm[0.4, 0.8] (P=4×10(-12)), but no association was observed for decaffeinated coffee intake. Finally, caffeine was also positively associated with SIF1LED 375 nm[0.6, 0.2] and SIF14LED 456 nm[0.4, 0.8] (P<0.0001) in the replication cohort. Caffeine contributes to SIF. The effect of rs1495741 on SIF appears to be partially independent of caffeine consumption. Because SIF and coffee intake are each associated with cardiovascular disease, our findings suggest that accounting for coffee and/or caffeine intake may improve risk prediction models for SIF and cardiovascular disease in individuals with diabetes.
    Full-text · Article · Jul 2015 · Diabetes Technology & Therapeutics
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    ABSTRACT: Studies have shown oxidized low-density lipoprotein to be associated with the incidence of proliferative retinopathy and other complications of type 1 diabetes mellitus. Because low-risk interventions are available to modify oxidized low-density lipoprotein, it is important to examine the relationships between this factor and the incidence of proliferative retinopathy and of macular edema, 2 important causes of visual impairment in people with type 1 diabetes. To determine the association of oxidized low-density lipoprotein with the worsening of diabetic retinopathy and the incidence of proliferative retinopathy and of macular edema. Of 996 participants with type 1 diabetes in the Wisconsin Epidemiologic Study of Diabetic Retinopathy, 730 were examined up to 4 times (1990-1992, 1994-1996, 2005-2007, and 2012-2014) over 24 years and had assays of oxidized low-density lipoprotein and fundus photographs gradable for diabetic retinopathy and macular edema. Analyses started July 2014 and ended February 2015. Worsening of diabetic retinopathy, incidence of proliferative diabetic retinopathy, and incidence of macular edema as assessed via grading of color stereo film fundus photographs. The levels of oxidized low-density lipoprotein collected from serum samples at the time of each examination were measured in 2013 and 2014 from frozen serum. The cohort at baseline had a mean (SD) level of oxidized low-density lipoprotein of 30.0 (8.5) U/L. While adjusting for duration of diabetes, glycated hemoglobin A1c level, and other factors, we found that neither the level of oxidized low-density lipoprotein at the beginning of a period nor the change in it over a certain period was associated with the incidence of proliferative diabetic retinopathy (hazard ratio [HR], 1.11 [95% CI, 0.91-1.35], P = .30; odds ratio [OR], 1.77 [95% CI, 0.99-3.17], P = .06), the incidence of macular edema (HR, 1.04 [95% CI, 0.83-1.29], P = .74; OR, 1.08 [95% CI, 0.44-2.61], P = .87), or the worsening of diabetic retinopathy (HR, 0.94 [95% CI, 0.83-1.07], P = .34; OR, 1.32 [95% CI, 0.83-2.09], P = .24). Our findings do not provide evidence for a relationship between increasing levels of serum oxidized low-density lipoprotein and the incidence of macular edema or the worsening of diabetic retinopathy in persons with type 1 diabetes. The potential increase in the HR for incident proliferative retinopathy, with an increase in oxidized low-density lipoprotein level over the preceding period, warrants further investigation of this relationship.
    No preview · Article · Jul 2015 · Jama Ophthalmology
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    Lizhen Xu · Andrew D. Paterson · Williams Turpin · Wei Xu
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    ABSTRACT: Typical data in a microbiome study consist of the operational taxonomic unit (OTU) counts that have the characteristic of excess zeros, which are often ignored by investigators. In this paper, we compare the performance of different competing methods to model data with zero inflated features through extensive simulations and application to a microbiome study. These methods include standard parametric and non-parametric models, hurdle models, and zero inflated models. We examine varying degrees of zero inflation, with or without dispersion in the count component, as well as different magnitude and direction of the covariate effect on structural zeros and the count components. We focus on the assessment of type I error, power to detect the overall covariate effect, measures of model fit, and bias and effectiveness of parameter estimations. We also evaluate the abilities of model selection strategies using Akaike information criterion (AIC) or Vuong test to identify the correct model. The simulation studies show that hurdle and zero inflated models have well controlled type I errors, higher power, better goodness of fit measures, and are more accurate and efficient in the parameter estimation. Besides that, the hurdle models have similar goodness of fit and parameter estimation for the count component as their corresponding zero inflated models. However, the estimation and interpretation of the parameters for the zero components differs, and hurdle models are more stable when structural zeros are absent. We then discuss the model selection strategy for zero inflated data and implement it in a gut microbiome study of > 400 independent subjects.
    Full-text · Article · Jul 2015 · PLoS ONE
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    ABSTRACT: Gene-based, pathway, and other multivariate association methods are motivated by the possibility of GxG and GxE interactions; however, accounting for such interactions is limited by the challenges associated with adequate modeling information. Here we propose an easy-to-implement joint location-scale (JLS) association testing framework for single-variant and multivariate analysis that accounts for interactions without explicitly modeling them. We apply the JLS method to a gene-set analysis of cystic fibrosis (CF) lung disease, which is influenced by multiple environmental and genetic factors. We identify and replicate an association between the constituents of the apical plasma membrane and CF lung disease (p = 0.0099 and p = 0.0180, respectively) and highlight a role for the SLC9A3-SLC9A3R1/2-EZR complex in contributing to CF lung disease. Many association studies could benefit from re-analysis with the JLS method that leverages complex genetic architecture for SNP, gene, and pathway identification. Analytical verification, simulation, and additional proof-of-principle applications support our approach. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · The American Journal of Human Genetics

  • No preview · Conference Paper · Jun 2015

  • No preview · Conference Paper · Jun 2015
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    Sarah A. Gagliano · Andrew D. Paterson · Michael E. Weale · Jo Knight
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    ABSTRACT: Background In silico models have recently been created in order to predict which genetic variants are more likely to contribute to the risk of a complex trait given their functional characteristics. However, there has been no comprehensive review as to which type of predictive accuracy measures and data visualization techniques are most useful for assessing these models. Methods We assessed the performance of the models for predicting risk using various methodologies, some of which include: receiver operating characteristic (ROC) curves, histograms of classification probability, and the novel use of the quantile-quantile plot. These measures have variable interpretability depending on factors such as whether the dataset is balanced in terms of numbers of genetic variants classified as risk variants versus those that are not. Results We conclude that the area under the curve (AUC) is a suitable starting place, and for models with similar AUCs, violin plots are particularly useful for examining the distribution of the risk scores. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1616-z) contains supplementary material, which is available to authorized users.
    Preview · Article · May 2015 · BMC Genomics

  • No preview · Conference Paper · May 2015

  • No preview · Conference Paper · May 2015
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    ABSTRACT: It has been suggested that inflammatory bowel disease (IBD) is due to a genetically determined abnormal interaction between gut immune responses and gut bacteria. In order to determine if the composition and diversity of gut microbiota are associated with host genetic makeup we assessed the stool microbiome in a cohort of 918 FDR of CD patients. The V4 hypervariable regions of 16S rRNA were sequenced from bacterial DNA extracted from the stool of 918 unrelated healthy Caucasian FDRs. MiSeq Sequences were processed using PANDAseq and the QIIME pipeline. Non-chimeric sequences were clustered into operational taxonomic units (OTUs) at 97.0% sequence identity using USEARCH and GreenGenes. Single nucleotide polymorphisms (SNPs) were determined with the HumanCoreEXOME chip with imputations using IMPUTE2 2.3.0 to the 1000 Genomes panel of March 2012. Associations between SNPs and phylotypes were estimated using linear regression adjusting for the total number of reads, age, sex, and the first three genetic principal components. Raw SNP p-values of <10-5 are presented. Overall, dominant phyla in these samples were Firmicutes (relative abundance of 64.2% ± 14.1, mean ± SD), Bacteroidetes (26.9% ± 15.0), and Actinobacteria (5.0% ± 5.2). 3,727,707 genetic markers with high quality were imputed. rs2882345, located in a non-coding region of chr 7 was significantly associated with bacterial diversity (p=4.8×10-7). No associations were observed among the 163 SNPs associated with IBD. However, a total of 146 SNPs were associated with the relative abundance of microbial phyla (p<10-6). The strongest signal observed was located on chr 12 with rs145366794 associated with the relative abundance of Firmicutes (p=6.2×10-9); however, its minor allele frequency was low (1.6%). SNPs in LINC01446 and CAPRIN1 were associated with the relative abundance of Actinobacteria (p=5.9×10-6), SNPs in PHLPP1 and MKL1 were associated with Bacteroidetes (p=5.9×10-6 and p=3.9×10-6), SNPs in RAB27B and PM20D1 as well as non-coding regions of chr 1 and 18 with Firmicutes (p=8.0×10-6), and SNPs in MET were associated with Proteobacteria (p=1.5×10-6). These results indicate that host genetic polymorphisms are associated with differences in intestinal microbiota diversity and composition at the phylum level in cohort of healthy FDR. These results differ from prior studies of microbiota in patients with CD, potentially indicating that genetic associations with microbiota are difficult to evaluate in the context of established inflammation. It remains to be shown if any of these genetic associations with microbiome differences are related to the risk of developing Crohn’s’ disease. Our results represent the largest study evaluating the association between host genetics and the microbiota and in asymptomatic individuals.
    No preview · Conference Paper · Apr 2015

  • No preview · Article · Apr 2015 · Gastroenterology
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    ABSTRACT: Non-progressive cerebellar ataxias are a rare group of disorders that comprise approximately 10% of static infantile encephalopathies. We report the identification of mutations in PMPCA in 17 patients from four families affected with cerebellar ataxia, including the large Lebanese family previously described with autosomal recessive cerebellar ataxia and short stature of Norman type and localized to chromosome 9q34 (OMIM #213200). All patients present with non-progressive cerebellar ataxia, and the majority have intellectual disability of variable severity. PMPCA encodes α-MPP, the alpha subunit of mitochondrial processing peptidase, the primary enzyme responsible for the maturation of the vast majority of nuclear-encoded mitochondrial proteins, which is necessary for life at the cellular level. Analysis of lymphoblastoid cells and fibroblasts from patients homozygous for the PMPCA p.Ala377Thr mutation and carriers demonstrate that the mutation impacts both the level of the alpha subunit encoded by PMPCA and the function of mitochondrial processing peptidase. In particular, this mutation impacts the maturation process of frataxin, the protein which is depleted in Friedreich ataxia. This study represents the first time that defects in PMPCA and mitochondrial processing peptidase have been described in association with a disease phenotype in humans. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Full-text · Article · Mar 2015 · Brain

Publication Stats

10k Citations
2,048.06 Total Impact Points

Institutions

  • 2000-2015
    • SickKids
      • Program in Genetics and Genome Biology
      Toronto, Ontario, Canada
  • 1995-2015
    • University of Toronto
      • • Hospital for Sick Children
      • • Sunnybrook Health Sciences Centre
      Toronto, Ontario, Canada
    • North York General Hospital
      North York, Ontario, Canada
  • 2003-2014
    • George Washington University
      Washington, Washington, D.C., United States
  • 2013
    • Queen's University
      • Department of Pathology and Molecular Medicine
      Kingston, Ontario, Canada
  • 1999-2000
    • Centre for Addiction and Mental Health
      Toronto, Ontario, Canada
  • 1998
    • Toronto Western Hospital
      Toronto, Ontario, Canada