Genizon Biosciences Inc.

Saint-Laurent, Canada

Genizon Biosciences Inc.

Saint-Laurent, Canada

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ELinghaus E.,University of Kiel | ELinghaus D.,University of Kiel | Stuart P.E.,University of Michigan | Nair R.P.,University of Michigan | And 32 more authors.
Nature Genetics | Year: 2010

Psoriasis is a multifactorial skin disease characterized by epidermal hyperproliferation and chronic inflaMation, the most coMon form of which is psoriasis vulgaris (PsV). We present a genome-wide aSociation analysis of 2,339,118 SNPs in 472 PsV cases and 1,146 controls from Germany, with foLow-up of the 147 most significant SNPs in 2,746 PsV cases and 4,140 controls from thrE independent replication panels. We identified an aSociation at TRAF3IP2 on 6q21 and genotyped two SNPs at this locus in two aDitional replication panels (the combined discovery and replication panels consisted of 6,487 cases and 8,037 controls; combined P = 2.36-10-10 for rs13210247 and combined P = 1.24-10-16 for rs33980500). About 15% of psoriasis cases develop psoriatic arthritis (PsA). A stratified analysis of our datasets including only PsA cases (1,922 cases compared to 8,037 controls, P = 4.57-10-12 for rs33980500) suGested that TRAF3IP2 represents a shared susceptibility for PsV and PsA. TRAF3IP2 encodes a protein involved in IL-17 signaling and which interacts with members of the Rel/NF-κB transcription factor family. © 2010 Nature America, Inc. All rights reserved.


Stevens A.,Royal Manchester Childrens Hospital | Clayton P.,Royal Manchester Childrens Hospital | Tato L.,University of Verona | Yoo H.W.,University of Ulsan | And 10 more authors.
Pharmacogenomics Journal | Year: 2014

Individual responses to growth hormone (GH) treatment are variable. Short-term generation of insulin-like growth factor-I (IGF-I) is recognized as a potential marker of sensitivity to GH treatment. This prospective, phase IV study used an integrated genomic analysis to identify markers associated with 1-month change in IGF-I (ΔIGF-I) following initiation of recombinant human (r-h)GH therapy in treatment-naïve children with GH deficiency (GHD) (n=166) or Turner syndrome (TS) (n=147). In both GHD and TS, polymorphisms in the cell-cycle regulator CDK4 were associated with 1-month ΔIGF-I (P<0.05). Baseline gene expression was also correlated with 1-month ΔIGF-I in both GHD and TS (r=0.3; P<0.01). In patients with low IGF-I responses, carriage of specific CDK4 alleles was associated with MAPK and glucocorticoid receptor signaling in GHD, and with p53 and Wnt signaling pathways in TS. Understanding the relationship between genomic markers and early changes in IGF-I may allow development of strategies to rapidly individualize r-hGH dose. © 2014 Macmillan Publishers Limited All rights reserved.


Ellinghaus D.,University of Kiel | Ellinghaus E.,University of Kiel | Nair R.P.,University of Michigan | Stuart P.E.,University of Michigan | And 26 more authors.
American Journal of Human Genetics | Year: 2012

Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 × 10 -8) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, p rs1250544 = 3.53 × 10 -8, 11q13 near PRDX5, p rs694739 = 3.71 × 10 -09, 22q11 at YDJC, p rs181359 = 8.02 × 10 -10). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, p rs4780355 = 4.99 × 10 -8). Refinement of association signals identified shared genome-wide significant associations for exonic SNPs at 10q22 (ZMIZ1) and in silico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci. © 2012 The American Society of Human Genetics.


Pidasheva S.,Genentech | Trifari S.,Genentech | Trifari S.,La Jolla Institute for Allergy and Immunology | Phillips A.,Genentech | And 12 more authors.
PLoS ONE | Year: 2011

Genome-wide association studies (GWAS) in several populations have demonstrated significant association of the IL23R gene with IBD (Crohn's disease (CD) and ulcerative colitis (UC)) and psoriasis, suggesting that perturbation of the IL-23 signaling pathway is relevant to the pathophysiology of these diseases. One particular variant, R381Q (rs11209026), confers strong protection against development of CD. We investigated the effects of this variant in primary T cells from healthy donors carrying IL23R R381 and IL23R Q381 haplotypes. Using a proprietary anti-IL23R antibody, ELISA, flow cytometry, phosphoflow and real-time RT-PCR methods, we examined IL23R expression and STAT3 phosphorylation and activation in response to IL-23. IL23R Q381 was associated with reduced STAT3 phosphorylation upon stimulation with IL-23 and decreased number of IL-23 responsive T-cells. We also observed slightly reduced levels of proinflammatory cytokine secretion in IL23R Q381 positive donors. Our study shows conclusively that IL23R Q381 is a loss-of-function allele, further strengthening the implication from GWAS results that the IL-23 pathway is pathogenic in human disease. This data provides an explanation for the protective role of R381Q in CD and may lead to the development of improved therapeutics for autoimmune disorders like CD. © 2011 Pidasheva et al.


Ellinghaus E.,University of Kiel | Stuart P.E.,University of Michigan | Ellinghaus D.,University of Kiel | Nair R.P.,University of Michigan | And 26 more authors.
Journal of Investigative Dermatology | Year: 2012

Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease affecting up to 30% of psoriasis vulgaris (PsV) cases and approximately 0.25 to 1% of the general population. To identify common susceptibility loci, we performed a meta-analysis of three imputed genome-wide association studies (GWAS) on psoriasis, stratified for PsA. A total of 1,160,703 single-nucleotide polymorphisms (SNPs) were analyzed in the discovery set consisting of 535 PsA cases and 3,432 controls from Germany, the United States, and Canada. We followed up two SNPs in 1,931 PsA cases and 6,785 controls comprising six independent replication panels from Germany, Estonia, the United States, and Canada. In the combined analysis, a genome-wide significant association was detected at 2p16 near the REL locus encoding c-Rel (rs13017599, P1.18 × 10 -8, odds ratio (OR)1.27, 95% confidence interval (CI)1.18-1.35). The rs13017599 polymorphism is known to associate with rheumatoid arthritis (RA), and another SNP near REL (rs702873) was recently implicated in PsV susceptibility. However, conditional analysis indicated that rs13017599, rather than rs702873, accounts for the PsA association at REL. We hypothesize that c-Rel, as a member of the Rel/NF-κB family, is associated with PsA in the context of disease pathways that involve other identified PsA and PsV susceptibility genes including TNIP1, TNFAIP3, and NFκBIA. © 2012 The Society for Investigative Dermatology.


Bradley W.E.C.,University of Montréal | Raelson J.V.,Genizon Biosciences Inc. | Dubois D.Y.,Genizon Biosciences Inc. | Godin E.,Genizon Biosciences Inc. | And 8 more authors.
PLoS ONE | Year: 2010

Background: We have examined the genomic distribution of large rare autosomal deletions in a sample of 440 parent-parent-child trios from the Quebec founder population (QFP) which was recruited for a study of Attention Deficit Hyperactivity Disorder. Methodology/Principal Findings: DNA isolated from blood was genotyped on Illumina Hap300 arrays. PennCNV combined with visual evaluation of images generated by the Beadstudio program was used to determine deletion boundary definition of sufficient precision to discern independent events, with near-perfect concordance between parent and child in about 98% of the 399 events detected in the offspring; the remaining 7 deletions were considered de novo. We defined several genomic regions of very high deletion frequency ('hotspots'), usually of 0.4-0.6 Mb in length where independent rare deletions were found at frequencies of up to 100 fold higher than the average for the genome as a whole. Five of the 7 de novo deletions were in these hotspots. The same hotspots were also observed in three other studies on members of the QFP, those with schizophrenia, with endometriosis and those from a longevity cohort. Conclusions/Significance: Nine of the 13 hotspots carry one gene (7 of which are very long), while the rest contain no known genes. All nine genes have been implicated in disease. The patterns of exon deletions support the proposed roles for some of these genes in human disease, such as NRXN1 and PARKIN, and suggest limited roles or no role at all, for others, including MACROD2 and CTNNA3. Our results also offer an alternative interpretation for the observations of deletions in tumors which have been proposed as reflecting tumor-suppressive activity of genes in these hotspots. © 2010 Bradley et al.


Merner N.D.,University of Montréal | Girard S.L.,University of Montréal | Catoire H.,University of Montréal | Bourassa C.V.,University of Montréal | And 19 more authors.
American Journal of Human Genetics | Year: 2012

Essential tremor (ET) is a common neurodegenerative disorder that is characterized by a postural or motion tremor. Despite a strong genetic basis, a gene with rare pathogenic mutations that cause ET has not yet been reported. We used exome sequencing to implement a simple approach to control for misdiagnosis of ET, as well as phenocopies involving sporadic and senile ET cases. We studied a large ET-affected family and identified a FUS p.Gln290 mutation as the cause of ET in this family. Further screening of 270 ET cases identified two additional rare missense FUS variants. Functional considerations suggest that the pathogenic effects of ET-specific FUS mutations are different from the effects observed when FUS is mutated in amyotrophic lateral sclerosis cases; we have shown that the ET FUS nonsense mutation is degraded by the nonsense-mediated-decay pathway, whereas amyotrophic lateral sclerosis FUS mutant transcripts are not. © 2012 The American Society of Human Genetics.


Bourassa C.V.,University of Montréal | Riviere J.-B.,University of Montréal | Dion P.A.,University of Montréal | Bernard G.,University of Montréal | And 9 more authors.
PLoS ONE | Year: 2011

Essential tremor (ET) is a complex genetic disorder for which no causative gene has been found. Recently, a genome-wide association study reported that two variants in the LINGO1 locus were associated to this disease. The aim of the present study was to test if this specific association could be replicated using a French-Canadian cohort of 259 ET patients and 479 ethnically matched controls. Our genotyping results lead us to conclude that no association exists between the key variant rs9652490 and ET (P corr = 1.00). © 2011 Bourassa, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Hu X.,Pfizer | Pickering E.,Pfizer | Liu Y.C.,Pfizer | Hall S.,Pfizer | And 8 more authors.
PLoS ONE | Year: 2011

Recent GWAS studies focused on uncovering novel genetic loci related to AD have revealed associations with variants near CLU, CR1, PICALM and BIN1. In this study, we conducted a genome-wide association study in an independent set of 1034 cases and 1186 controls using the Illumina genotyping platforms. By coupling our data with available GWAS datasets from the ADNI and GenADA, we replicated the original associations in both PICALM (rs3851179) and CR1 (rs3818361). The PICALM variant seems to be non-significant after we adjusted for APOE e4 status. We further tested our top markers in 751 independent cases and 751 matched controls. Besides the markers close to the APOE locus, a marker (rs12989701) upstream of BIN1 locus was replicated and the combined analysis reached genome-wide significance level (p = 5E-08). We combined our data with the published Harold et al. study and meta-analysis with all available 6521 cases and 10360 controls at the BIN1 locus revealed two significant variants (rs12989701, p = 1.32E-10 and rs744373, p = 3.16E-10) in limited linkage disequilibrium (r2 = 0.05) with each other. The independent contribution of both SNPs was supported by haplotype conditional analysis. We also conducted multivariate analysis in canonical pathways and identified a consistent signal in the downstream pathways targeted by Gleevec (P = 0.004 in Pfizer; P = 0.028 in ADNI and P = 0.04 in GenADA). We further tested variants in CLU, PICALM, BIN1 and CR1 for association with disease progression in 597 AD patients where longitudinal cognitive measures are sufficient. Both the PICALM and CLU variants showed nominal significant association with cognitive decline as measured by change in Clinical Dementia Rating-sum of boxes (CDR-SB) score from the baseline but did not pass multiple-test correction. Future experiments will help us better understand potential roles of these genetic loci in AD pathology. © 2011 Hu et al.


Chen M.-H.,Boston University | Van Eerdewegh P.,Genizon Biosciences Inc. | Vincent Q.B.,University of Paris Descartes | Alcais A.,University of Paris Descartes | And 2 more authors.
Human Heredity | Year: 2010

Linkage analysis is often followed by association mapping to localize disease variants. In this paper, we evaluate approaches to determine how much of the observed linkage evidence, namely the identity-by-descent (IBD) sharing at the linkage peak, is explained by associated SNPs. We study several methods: Homozygote Sharing Tests (HST), Genotype Identity-by-Descent Sharing Test (GIST), and a permutation approach. We also propose a new approach, HSTMLB, combining HST and the Maximum Likelihood Binomial (MLB) linkage statistic. These methods can identify SNPs partially explaining the linkage peak, but only HST and HSTMLB can identify SNPs that do not fully explain the linkage evidence and be applied to multiple-SNPs. We contrast these methods with the association tests implemented in the software LAMP. In our simulations, GIST is more powerful at finding SNPs that partially explain the linkage peak, while HST and HSTMLB are equally powerful at identifying SNPs that do not fully explain the linkage peak. When applied to the North American Rheumatoid Arthritis Consortium data, HST and HSTMLB identify marker pairs that may fully explain the linkage peak on chromosome 6. In conclusion, HST and HSTMLB provide simple and flexible tools to identify SNPs that explain the IBD sharing at the linkage peak. Copyright © 2009 S. Karger AG, Basel.

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