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Dive into the research topics where Jorge R. Oksenberg is active.

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Featured researches published by Jorge R. Oksenberg.


Nature | 2009

Common variants on chromosome 6p22.1 are associated with schizophrenia

Jianxin Shi; Douglas F. Levinson; Jubao Duan; Alan R. Sanders; Yonglan Zheng; Itsik Pe'er; Frank Dudbridge; Peter Holmans; Alice S. Whittemore; Bryan J. Mowry; Ann Olincy; Farooq Amin; C. Robert Cloninger; Jeremy M. Silverman; Nancy G. Buccola; William Byerley; Donald W. Black; Raymond R. Crowe; Jorge R. Oksenberg; Daniel B. Mirel; Kenneth S. Kendler; Robert Freedman; Pablo V. Gejman

Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5–1%, with high heritability (80–85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 × 10-9). This region includes a histone gene cluster and several immunity-related genes—possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.


Nature Genetics | 2009

Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

Philip L. De Jager; Xiaoming Jia; Joanne Wang; Paul I. W. de Bakker; Linda Ottoboni; Neelum T. Aggarwal; Laura Piccio; Soumya Raychaudhuri; Dong Tran; Cristin Aubin; Rebeccah Briskin; Susan Romano; Sergio E. Baranzini; Jacob L. McCauley; Margaret A. Pericak-Vance; Jonathan L. Haines; Rachel A. Gibson; Yvonne Naeglin; Bernard M. J. Uitdehaag; Paul M. Matthews; Ludwig Kappos; Chris H. Polman; Wendy L. McArdle; David P. Strachan; Denis A. Evans; Anne H. Cross; Mark J. Daly; Alastair Compston; Stephen Sawcer; Howard L. Weiner

We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 × 10−11), IRF8 (P = 3.73 × 10−9) and CD6 (P = 3.79 × 10−9). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.


Neuron | 2006

THE NEUROBIOLOGY OF MULTIPLE SCLEROSIS: GENES, INFLAMMATION, AND NEURODEGENERATION

Stephen L. Hauser; Jorge R. Oksenberg

The autoimmune model of multiple sclerosis (MS) pathogenesis provided for many years a useful but incomplete conceptual framework for understanding the complex array of factors that lead to the loss of immune homeostasis, myelin and axonal injury, and progressive neurological symptoms. The availability of novel tools in molecular neurogenetics and increasingly sophisticated neuroimaging technologies, together with the revitalization of MS neuropathology, has created a new paradigm for the multidisciplinary study of this disease. This is reflected by the growing resolution of the MS genomic map, discovery of delicate inflammatory networks that are perturbed in MS, identification of mediators of demyelination, and recognition that cumulative axonal loss and neuronal injury are the histological correlates of neurological disability. Together, these advances have set the stage for the development of therapeutic approaches designed to target the demyelinating and neurodegenerative components of the disease and promote repair.


Nature Genetics | 2007

Interleukin 7 receptor α chain ( IL7R ) shows allelic and functional association with multiple sclerosis

Simon G. Gregory; Silke Schmidt; Puneet Seth; Jorge R. Oksenberg; John Hart; Angela Prokop; Stacy J. Caillier; Maria Ban; An Goris; Lisa F. Barcellos; Robin Lincoln; Jacob L. McCauley; Stephen Sawcer; D. A. S. Compston; Bénédicte Dubois; Stephen L. Hauser; Mariano A. Garcia-Blanco; Margaret A. Pericak-Vance; Jonathan L. Haines

Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor α chain ( IL7R ) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 × 10−7). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.


Nature | 2010

Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis

Sergio E. Baranzini; Joann Mudge; Jennifer C. van Velkinburgh; Pouya Khankhanian; Irina Khrebtukova; Neil Miller; Lu Zhang; Andrew D. Farmer; Callum J. Bell; Ryan W. Kim; Gregory D. May; Jimmy E. Woodward; Stacy J. Caillier; Joseph P. McElroy; Refujia Gomez; Marcelo J. Pando; Leonda E. Clendenen; Elena E. Ganusova; Faye D. Schilkey; Thiruvarangan Ramaraj; Omar Khan; Jim J. Huntley; Shujun Luo; Pui-Yan Kwok; Thomas D. Wu; Gary P. Schroth; Jorge R. Oksenberg; Stephen L. Hauser; Stephen F. Kingsmore

Monozygotic or ‘identical’ twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4+ lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among ∼3.6 million single nucleotide polymorphisms (SNPs) or ∼0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of ∼19,000 genes in CD4+ T cells. Only 2 to 176 differences in the methylation of ∼2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to ∼800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported.


Nature | 1993

Selection for T-cell receptor Vβ-Dβ-Jβ gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis

Jorge R. Oksenberg; Michael A. Panzara; Ann B. Begovich; Dennis J. Mitchell; Henry A. Erlich; Ronald S. Murray; Richard Shimonkevitz; Martina A. Sherritt; Jonathan B. Rothbard; Claude C.A. Bernard; Lawrence Steinman

MULTIPLE sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system in which a restricted cellular immune response has been observed. In order to establish whether such T cell responses are likely to be antigen-specific particularly with regard to myelin basic protein (MBP), we analysed T-cell receptor (TCR) gene rearrangements directly from MS brain plaques, using the polymerase chain reaction on reverse transcribed messenger RNA, and compared these with TCR of previously described MBP-specific T cell clones from MS and the rat model experimental allergic encephalomyelitis. Rearranged Vβ5.2 genes were detected in the brains of all patients who were HLA DRB1*1501, DQA1*0102, DQB1*0602, DPB1*0401. The Vβ5.2–Dβ–Jβ sequences in these MS brain plaques revealed five motifs. One of the common motifs was identical to that described for the VDJ region of a Vβ5.2 T-cell clone. This clone was from an MS patient who was HLA DRB1*1501, DQB1*0602, DPB1*0401, and it was cytotoxic towards targets containing the MBP peptide 89–106 (ref. 1). The deduced amino-acid sequence of this VDJ rearrangement, Leu-Arg-Gly, has also been described in rat T cells cloned from experimental allergic encephalomyelitis lesions, which are specific for MBP peptide 87–99 (ref. 2). VDJ sequences with specificity for this MBP epitope constitute a large fraction (40%) of the TCR Vβ5.2 N(D)N rearrangements in MS lesions. The capacity of rat T cells with these VDJ sequences to cause experimental allergic encephalomyelitis2 and the prevalence of such sequences in demyelinated human lesions indicate that T cells with this rearranged TCR may be critical in MS.


Human Molecular Genetics | 2009

Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis

Sergio E. Baranzini; Joanne Wang; Rachel A. Gibson; Nicholas W. Galwey; Yvonne Naegelin; Frederik Barkhof; Ernst Wilhelm Radue; Raija L.P. Lindberg; Bernard Uitdehaag; Michael R. Johnson; Aspasia Angelakopoulou; Leslie Hall; Jill C. Richardson; Rab K. Prinjha; Achim Gass; Jeroen J. G. Geurts; Madeleine H. Sombekke; Hugo Vrenken; Pamela Qualley; Robin Lincoln; Refujia Gomez; Stacy J. Caillier; Michaela F. George; Hourieh Mousavi; Rosa Guerrero; Darin T. Okuda; Bruce Cree; Ari J. Green; Emmanuelle Waubant; Douglas S. Goodin

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.


Human Molecular Genetics | 2009

Pathway and network-based analysis of genome-wide association studies in multiple sclerosis

Sergio E. Baranzini; Nicholas W. Galwey; Joanne Wang; Pouya Khankhanian; Raija L.P. Lindberg; Daniel Pelletier; Wen Wu; Bernard M. J. Uitdehaag; Ludwig Kappos; Chris H. Polman; Paul M. Matthews; Stephen L. Hauser; Rachel A. Gibson; Jorge R. Oksenberg; Michael R. Barnes

Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Typically, the number of markers in which the evidence for association exceeds the genome-wide significance threshold is very small, and markers that do not exceed this threshold are generally neglected. Classical statistical analysis of these datasets in MS revealed genes with known immunological functions. However, many of the markers showing modest association may represent false negatives. We hypothesize that certain combinations of genes flagged by these markers can be identified if they belong to a common biological pathway. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association (P < 0.05). Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance. These sub-networks, and others generated at random as a control, were categorized for membership of biological pathways. GWAS from eight other diseases were analyzed to assess the specificity of the pathways identified. In the MS datasets, we identified sub-networks of genes from several immunological pathways including cell adhesion, communication and signaling. Remarkably, neural pathways, namely axon-guidance and synaptic potentiation, were also over-represented in MS. In addition to the immunological pathways previously identified, we report here for the first time the potential involvement of neural pathways in MS susceptibility.


Proceedings of the National Academy of Sciences of the United States of America | 2010

Genome-wide patterns of population structure and admixture in West Africans and African Americans

Katarzyna Bryc; Adam Auton; Matthew R. Nelson; Jorge R. Oksenberg; Stephen L. Hauser; Scott M. Williams; Alain Froment; Jean-Marie Bodo; Charles Wambebe; Sarah A. Tishkoff; Carlos Bustamante

Quantifying patterns of population structure in Africans and African Americans illuminates the history of human populations and is critical for undertaking medical genomic studies on a global scale. To obtain a fine-scale genome-wide perspective of ancestry, we analyze Affymetrix GeneChip 500K genotype data from African Americans (n = 365) and individuals with ancestry from West Africa (n = 203 from 12 populations) and Europe (n = 400 from 42 countries). We find that population structure within the West African sample reflects primarily language and secondarily geographical distance, echoing the Bantu expansion. Among African Americans, analysis of genomic admixture by a principal component-based approach indicates that the median proportion of European ancestry is 18.5% (25th–75th percentiles: 11.6–27.7%), with very large variation among individuals. In the African-American sample as a whole, few autosomal regions showed exceptionally high or low mean African ancestry, but the X chromosome showed elevated levels of African ancestry, consistent with a sex-biased pattern of gene flow with an excess of European male and African female ancestry. We also find that genomic profiles of individual African Americans afford personalized ancestry reconstructions differentiating ancient vs. recent European and African ancestry. Finally, patterns of genetic similarity among inferred African segments of African-American genomes and genomes of contemporary African populations included in this study suggest African ancestry is most similar to non-Bantu Niger-Kordofanian-speaking populations, consistent with historical documents of the African Diaspora and trans-Atlantic slave trade.


Nature Reviews Genetics | 2008

The genetics of multiple sclerosis: SNPs to pathways to pathogenesis

Jorge R. Oksenberg; Sergio E. Baranzini; Stephen Sawcer; Stephen L. Hauser

Multiple sclerosis (MS) is an autoimmune demyelinating disease and a common cause of neurological disability in young adults. The modest heritability of MS reflects complex genetic effects and multifaceted gene–environment interactions. The human leukocyte antigen (HLA) region is the strongest susceptibility locus for MS, but a genome-wide association study recently identified new susceptibility genes. Progress in high-throughput genotyping and sequencing technologies and a better understanding of the structural organization of the human genome, together with powerful brain-imaging techniques that refine the phenotype, suggest that the tools could finally exist to identify the full set of genes influencing the pathogenesis of MS.

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Jonathan L. Haines

Case Western Reserve University

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Bruce Cree

University of California

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