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7 results on '"Sleiman, Patrick MA"'

1. Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes

Author

Glessner, Joseph T, Ningappa, Mylarappa B, Ngo, Kim A, Zahid, Maliha, So, Juhoon, Higgs, Brandon W, Sleiman, Patrick MA, Narayanan, Tejaswini, Ranganathan, Sarangarajan, March, Michael, Prasadan, Krishna, Vaccaro, Courtney, Reyes-Mugica, Miguel, Velazquez, Jeremy, Salgado, Claudia M, Ebrahimkhani, Mo R, Schmitt, Lori, Rajasundaram, Dhivyaa, Paul, Morgan, Pellegrino, Renata, Gittes, George K, Li, Dong, Wang, Xiang, Billings, Jonathan, Squires, Robert, Ashokkumar, Chethan, Sharif, Khalid, Kelly, Deirdre, Dhawan, Anil, Horslen, Simon, Lo, Cecilia W, Shin, Donghun, Subramaniam, Shankar, Hakonarson, Hakon, and Sindhi, Rakesh

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Digestive Diseases, Human Genome, Congenital Structural Anomalies, Prevention, Liver Disease, Infant Mortality, Pediatric, Rare Diseases, Perinatal Period - Conditions Originating in Perinatal Period, Chronic Liver Disease and Cirrhosis, Aetiology, 2.1 Biological and endogenous factors, Child, Animals, Mice, Humans, Biliary Atresia, Genome-Wide Association Study, Genetic Predisposition to Disease, Zebrafish, Canada, Ciliogenesis, Polygenic Susceptibility, Portal Vein, Tube Morphogenesis, Vascular Development, Public Health and Health Services, Gastroenterology & Hepatology, Clinical sciences
Abstract

Background & aimsBiliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA.MethodsWe performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models.ResultsA GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p = 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p = 1.34E-7), both supported by credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA was associated with 6,005 SNPs in 102 CPLANE genes (p = 5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants (allele frequency

Published
2023

2. Genetic correlations among psychiatric and immune‐related phenotypes based on genome‐wide association data

Author

Tylee, Daniel S, Sun, Jiayin, Hess, Jonathan L, Tahir, Muhammad A, Sharma, Esha, Malik, Rainer, Worrall, Bradford B, Levine, Andrew J, Martinson, Jeremy J, Nejentsev, Sergey, Speed, Doug, Fischer, Annegret, Mick, Eric, Walker, Brian R, Crawford, Andrew, Grant, Struan FA, Polychronakos, Constantin, Bradfield, Jonathan P, Sleiman, Patrick MA, Hakonarson, Hakon, Ellinghaus, Eva, Elder, James T, Tsoi, Lam C, Trembath, Richard C, Barker, Jonathan N, Franke, Andre, Dehghan, Abbas, Team, The 23 and Me Research, Consortium, The Inflammation Working Group of the CHARGE, Consortium, The METASTROKE Consortium of the International Stroke Genetics, Registry, The Netherlands Twin, Group, The neuroCHARGE Working, Consortium, The Obsessive Compulsive and Tourette Syndrome Working Group of the Psychiatric Genomics, Faraone, Stephen V, and Glatt, Stephen J

Subjects
Pharmacology and Pharmaceutical Sciences, Biological Sciences, Biomedical and Clinical Sciences, Genetics, Serious Mental Illness, Human Genome, Genetic Testing, Brain Disorders, Schizophrenia, Digestive Diseases, Prevention, Mental Health, Clinical Research, Autoimmune Disease, 2.1 Biological and endogenous factors, Aetiology, Mental health, Autoimmune Diseases, Comorbidity, Databases, Factual, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Mental Disorders, Multifactorial Inheritance, Polymorphism, Single Nucleotide, White People, allergy, anorexia nervosa, attention deficit-hyperactivity disorder, autoimmune disorder, bipolar disorder, celiac disease, childhood ear infection, C-reactive protein, Crohn's disease, genetic correlation, genome-wide association, hypothyroidism, major depression, neuroticism, obsessive schizophrenia, primary biliary cirrhosis, rheumatoid arthritis, smoking, systemic lupus erythematosus, Tourette syndrome, tuberculosis susceptibility, type 1 diabetes, ulcerative colitis, and Me Research Team, Inflammation Working Group of the CHARGE Consortium, METASTROKE Consortium of the International Stroke Genetics Consortium, Netherlands Twin Registry, neuroCHARGE Working Group, Obsessive Compulsive and Tourette Syndrome Working Group of the Psychiatric Genomics Consortium, Clinical Sciences, Neurosciences, Clinical sciences
Abstract

Individuals with psychiatric disorders have elevated rates of autoimmune comorbidity and altered immune signaling. It is unclear whether these altered immunological states have a shared genetic basis with those psychiatric disorders. The present study sought to use existing summary-level data from previous genome-wide association studies to determine if commonly varying single nucleotide polymorphisms are shared between psychiatric and immune-related phenotypes. We estimated heritability and examined pair-wise genetic correlations using the linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics methods. Using LDSC, we observed significant genetic correlations between immune-related disorders and several psychiatric disorders, including anorexia nervosa, attention deficit-hyperactivity disorder, bipolar disorder, major depression, obsessive compulsive disorder, schizophrenia, smoking behavior, and Tourette syndrome. Loci significantly mediating genetic correlations were identified for schizophrenia when analytically paired with Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus, and ulcerative colitis. We report significantly correlated loci and highlight those containing genome-wide associations and candidate genes for respective disorders. We also used the LDSC method to characterize genetic correlations among the immune-related phenotypes. We discuss our findings in the context of relevant genetic and epidemiological literature, as well as the limitations and caveats of the study.

Published
2018

5. Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations.

Author

Li, Yun Rose, Glessner, Joseph T, Coe, Bradley P, Li, Jin, Mohebnasab, Maede, Chang, Xiao, Connolly, John, Kao, Charlly, Wei, Zhi, Bradfield, Jonathan, Kim, Cecilia, Hou, Cuiping, Khan, Munir, Mentch, Frank, Qiu, Haijun, Bakay, Marina, Cardinale, Christopher, Lemma, Maria, Abrams, Debra, Bridglall-Jhingoor, Andrew, Behr, Meckenzie, Harrison, Shanell, Otieno, George, Thomas, Alexandria, Wang, Fengxiang, Chiavacci, Rosetta, Wu, Lawrence, Hadley, Dexter, Goldmuntz, Elizabeth, Elia, Josephine, Maris, John, Grundmeier, Robert, Devoto, Marcella, Keating, Brendan, March, Michael, Pellagrino, Renata, Grant, Struan FA, Sleiman, Patrick MA, Li, Mingyao, Eichler, Evan E, Hakonarson, Hakon, Li, Yun Rose, Glessner, Joseph T, Coe, Bradley P, Li, Jin, Mohebnasab, Maede, Chang, Xiao, Connolly, John, Kao, Charlly, Wei, Zhi, Bradfield, Jonathan, Kim, Cecilia, Hou, Cuiping, Khan, Munir, Mentch, Frank, Qiu, Haijun, Bakay, Marina, Cardinale, Christopher, Lemma, Maria, Abrams, Debra, Bridglall-Jhingoor, Andrew, Behr, Meckenzie, Harrison, Shanell, Otieno, George, Thomas, Alexandria, Wang, Fengxiang, Chiavacci, Rosetta, Wu, Lawrence, Hadley, Dexter, Goldmuntz, Elizabeth, Elia, Josephine, Maris, John, Grundmeier, Robert, Devoto, Marcella, Keating, Brendan, March, Michael, Pellagrino, Renata, Grant, Struan FA, Sleiman, Patrick MA, Li, Mingyao, Eichler, Evan E, and Hakonarson, Hakon

Abstract

Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.

Published
2019

6. Genetic sharing and heritability of paediatric age of onset autoimmune diseases.

Author

Li, Yun R, Zhao, Sihai D, Li, Jin, Bradfield, Jonathan P, Mohebnasab, Maede, Steel, Laura, Kobie, Julie, Abrams, Debra J, Mentch, Frank D, Glessner, Joseph T, Guo, Yiran, Wei, Zhi, Connolly, John J, Cardinale, Christopher J, Bakay, Marina, Li, Dong, Maggadottir, S Melkorka, Thomas, Kelly A, Qui, Haijun, Chiavacci, Rosetta M, Kim, Cecilia E, Wang, Fengxiang, Snyder, James, Flatø, Berit, Førre, Øystein, Denson, Lee A, Thompson, Susan D, Becker, Mara L, Guthery, Stephen L, Latiano, Anna, Perez, Elena, Resnick, Elena, Strisciuglio, Caterina, Staiano, Annamaria, Miele, Erasmo, Silverberg, Mark S, Lie, Benedicte A, Punaro, Marilynn, Russell, Richard K, Wilson, David C, Dubinsky, Marla C, Monos, Dimitri S, Annese, Vito, Munro, Jane E, Wise, Carol, Chapel, Helen, Cunningham-Rundles, Charlotte, Orange, Jordan S, Behrens, Edward M, Sullivan, Kathleen E, Kugathasan, Subra, Griffiths, Anne M, Satsangi, Jack, Grant, Struan FA, Sleiman, Patrick MA, Finkel, Terri H, Polychronakos, Constantin, Baldassano, Robert N, Luning Prak, Eline T, Ellis, Justine A, Li, Hongzhe, Keating, Brendan J, Hakonarson, Hakon, Li, Yun R, Zhao, Sihai D, Li, Jin, Bradfield, Jonathan P, Mohebnasab, Maede, Steel, Laura, Kobie, Julie, Abrams, Debra J, Mentch, Frank D, Glessner, Joseph T, Guo, Yiran, Wei, Zhi, Connolly, John J, Cardinale, Christopher J, Bakay, Marina, Li, Dong, Maggadottir, S Melkorka, Thomas, Kelly A, Qui, Haijun, Chiavacci, Rosetta M, Kim, Cecilia E, Wang, Fengxiang, Snyder, James, Flatø, Berit, Førre, Øystein, Denson, Lee A, Thompson, Susan D, Becker, Mara L, Guthery, Stephen L, Latiano, Anna, Perez, Elena, Resnick, Elena, Strisciuglio, Caterina, Staiano, Annamaria, Miele, Erasmo, Silverberg, Mark S, Lie, Benedicte A, Punaro, Marilynn, Russell, Richard K, Wilson, David C, Dubinsky, Marla C, Monos, Dimitri S, Annese, Vito, Munro, Jane E, Wise, Carol, Chapel, Helen, Cunningham-Rundles, Charlotte, Orange, Jordan S, Behrens, Edward M, Sullivan, Kathleen E, Kugathasan, Subra, Griffiths, Anne M, Satsangi, Jack, Grant, Struan FA, Sleiman, Patrick MA, Finkel, Terri H, Polychronakos, Constantin, Baldassano, Robert N, Luning Prak, Eline T, Ellis, Justine A, Li, Hongzhe, Keating, Brendan J, and Hakonarson, Hakon

Abstract

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.

Published
2015

7. Multi-ethnic genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Author

Paternoster, Lavinia, Standl, Marie, Waage, Johannes, Baurecht, Hansjörg, Hotze, Melanie, Strachan, David P, Curtin, John A, Bønnelykke, Klaus, Tian, Chao, Takahashi, Atsushi, Esparza-Gordillo, Jorge, Alves, Alexessander Couto, Thyssen, Jacob P, den Dekker, Herman T, Ferreira, Manuel A, Altmaier, Elisabeth, Sleiman, Patrick MA, Xiao, Feng Li, Gonzalez, Juan R, Marenholz, Ingo, Kalb, Birgit, Yanes, Maria Pino, Xu, Cheng-Jian, Carstensen, Lisbeth, Groen-Blokhuis, Maria M, Venturini, Cristina, Pennell, Craig E, Barton, Sheila J, Levin, Albert M, Curjuric, Ivan, Bustamante, Mariona, Kreiner-Møller, Eskil, Lockett, Gabrielle A, Bacelis, Jonas, Bunyavanich, Supinda, Myers, Rachel A, Matanovic, Anja, Kumar, Ashish, Tung, Joyce Y, Hirota, Tomomitsu, Kubo, Michiaki, McArdle, Wendy L, Henderson, A J, Kemp, John P, Zheng, Jie, Smith, George Davey, Rüschendorf, Franz, Bauerfeind, Anja, Lee-Kirsch, Min Ae, Arnold, Andreas, Homuth, Georg, Schmidt, Carsten O, Mangold, Elisabeth, Cichon, Sven, Keil, Thomas, Rodríguez, Elke, Peters, Annette, Franke, Andre, Lieb, Wolfgang, Novak, Natalija, Fölster-Holst, Regina, Horikoshi, Momoko, Pekkanen, Juha, Sebert, Sylvain, Husemoen, Lise L, Grarup, Niels, de Jongste, Johan C, Rivadeneira, Fernando, Hofman, Albert, Jaddoe, Vincent WV, Pasmans, Suzanne GMA, Elbert, Niels J, Uitterlinden, André G, Marks, Guy B, Thompson, Philip J, Matheson, Melanie C, Robertson, Colin F, Ried, Janina S, Li, Jin, Zuo, Xian Bo, Zheng, Xiao Dong, Yin, Xian Yong, Sun, Liang Dan, McAleer, Maeve A, O'Regan, Grainne M, Fahy, Caoimhe MR, Campbell, Linda E, Macek, Milan, Kurek, Michael, Hu, Donglei, Eng, Celeste, Postma, Dirkje S, Feenstra, Bjarke, Geller, Frank, Hottenga, Jouke Jan, Middeldorp, Christel M, Hysi, Pirro, Bataille, Veronique, Spector, Tim, Tiesler, Carla MT, Thiering, Elisabeth, Pahukasahasram, Badri, Yang, James J, Imboden, Medea, Huntsman, Scott, Vilor-Tejedor, Natàlia, Relton, Caroline L, Myhre, Ronny, Nystad, Wenche, Custovic, Adnan, Weiss, Scott T, Meyers, Deborah A, Söderhäll, Cilla, Melén, Erik, Ober, Carole, Raby, Benjamin A, Simpson, Angela, Jacobsson, Bo, Holloway, John W, Bisgaard, Hans, Sunyer, Jordi, Hensch, Nicole M Probst, Williams, L Keoki, Godfrey, Keith M, Wang, Carol A, Boomsma, Dorret I, Melbye, Mads, Koppelman, Gerard H, Jarvis, Deborah, McLean, WH Irwin, Irvine, Alan D, Zhang, Xue Jun, Hakonarson, Hakon, Gieger, Christian, Burchard, Esteban G, Martin, Nicholas G, Duijts, Liesbeth, Linneberg, Allan, Jarvelin, Marjo-Riitta, Noethen, Markus M, Lau, Susanne, Hübner, Norbert, Lee, Young-Ae, Tamari, Mayumi, Hinds, David A, Glass, Daniel, Brown, Sara J, Heinrich, Joachim, Evans, David M, and Weidinger, Stephan

Abstract

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified 10 novel risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with novel secondary signals at 4 of these). Notably, the new loci include candidate genes with roles in regulation of innate host defenses and T-cell function, underscoring the important contribution of (auto-)immune mechanisms to atopic dermatitis pathogenesis.

Published
2015
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