Publications by authors named "Ariel Darvasi"

64 Publications

Novel ultra-rare exonic variants identified in a founder population implicate cadherins in schizophrenia.

Neuron 2021 05 22;109(9):1465-1478.e4. Epub 2021 Mar 22.

Department of Computer Science, Columbia University, New York, NY 10027, USA; Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA. Electronic address:

The identification of rare variants associated with schizophrenia has proven challenging due to genetic heterogeneity, which is reduced in founder populations. In samples from the Ashkenazi Jewish population, we report that schizophrenia cases had a greater frequency of novel missense or loss of function (MisLoF) ultra-rare variants (URVs) compared to controls, and the MisLoF URV burden was inversely correlated with polygenic risk scores in cases. Characterizing 141 "case-only" genes (MisLoF URVs in ≥3 cases with none in controls), the cadherin gene set was associated with schizophrenia. We report a recurrent case mutation in PCDHA3 that results in the formation of cytoplasmic aggregates and failure to engage in homophilic interactions on the plasma membrane in cultured cells. Modeling purifying selection, we demonstrate that deleterious URVs are greatly overrepresented in the Ashkenazi population, yielding enhanced power for association studies. Identification of the cadherin/protocadherin family as risk genes helps specify the synaptic abnormalities central to schizophrenia.
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http://dx.doi.org/10.1016/j.neuron.2021.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177045PMC
May 2021

Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals.

Diabetologia 2018 10 16;61(10):2180-2188. Epub 2018 Jul 16.

Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.

Aims/hypothesis: Wolfram syndrome is a rare, autosomal recessive syndrome characterised by juvenile-onset diabetes and optic atrophy and is caused by bi-allelic mutations in the WFS1 gene. In a recent sequencing study, an individual with juvenile-onset diabetes was observed to be homozygous for a rare missense variant (c.1672C>T, p.R558C) in the WFS1 gene. The aim of this study was to perform the genetic characterisation of this variant and to determine whether it is causal for young-onset diabetes and Wolfram syndrome.

Methods: We analysed the allele frequency of the missense variant in multiple variant databases. We genotyped the variant in 475 individuals with type 1 diabetes and 2237 control individuals of Ashkenazi Jewish ancestry and analysed the phenotypes of homozygotes. We also investigated the association of this variant with risk for type 2 diabetes using genotype and sequence data for type 2 diabetes cases and controls.

Results: The missense variant demonstrated an allele frequency of 1.4% in individuals of Ashkenazi Jewish ancestry, 60-fold higher than in other populations. Genotyping of this variant in 475 individuals diagnosed with type 1 diabetes identified eight homozygotes compared with none in 2237 control individuals (genotype relative risk 135.3, p = 3.4 × 10). The age at diagnosis of diabetes for these eight individuals (17.8 ± 8.3 years) was several times greater than for typical Wolfram syndrome (5 ± 4 years). Further, optic atrophy was observed in only one of the eight individuals, while another individual had the Wolfram syndrome-relevant phenotype of neurogenic bladder. Analysis of sequence and genotype data in two case-control cohorts of Ashkenazi ancestry demonstrated that this variant is also associated with an increased risk of type 2 diabetes in heterozygotes (OR 1.81, p = 0.004).

Conclusions/interpretation: We have identified a low-frequency coding variant in the WFS1 gene that is enriched in Ashkenazi Jewish individuals and causes a mild form of Wolfram syndrome characterised by young-onset diabetes and reduced penetrance for optic atrophy. This variant should be considered for genetic testing in individuals of Ashkenazi ancestry diagnosed with young-onset non-autoimmune diabetes and should be included in Ashkenazi carrier screening panels.
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http://dx.doi.org/10.1007/s00125-018-4690-3DOI Listing
October 2018

Facilitating complex DNA mixture interpretation by sequencing highly polymorphic haplotypes.

Forensic Sci Int Genet 2018 07 2;35:136-140. Epub 2018 May 2.

Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel.

Interpretation of complex DNA mixtures is an ongoing challenge in the field of forensic genetics. Commonly used STR markers are quite polymorphic, enabling very high statistical association between a single source DNA profile from a crime scene and a matching suspect. STR typing of low order mixtures with two and three contributors also commonly produces high statistical association for a contributor, using current interpretation software. However higher order mixtures, with four contributors or more, are more challenging. Shared alleles among the many contributors may complicate the correct assessment of the number of contributors to a mixture and decreases the statistical support for inclusion of contributors. Recently, there is a rising use of massively parallel sequencing for forensic applications, and markers such as SNPs and short haplotypes are receiving more attention. However, these markers are even less polymorphic than autosomal STRs and are not suitable for complex mixture interpretation. We propose to use a different panel of haplotype markers, which contain many SNPs and are very polymorphic. These markers can be sequenced either by standard sequencing technologies or by a new instrument called MinION that sequences DNA as it passes through a nanopore. This instrument is very small and can sequence long stretches of DNA, but suffers from high error rate. We present a method for calling haplotype alleles facing high error rate, and use simulation to test its robustness. We also calculate likelihood ratio (LR) between propositions of contribution and non-contribution for individuals that do, and do not, contribute to various complex DNA mixtures. Our results indicate that the correct alleles can be identified in a mixture, despite the high sequencing error rate, and that contributors get high LR (>10) even in complex mixtures with up to five contributors. Non-contributors receive a very small LR, below 1 in most cases (>98%), which support their exclusion as possible donors to the complex DNA mixtures.
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http://dx.doi.org/10.1016/j.fsigen.2018.05.001DOI Listing
July 2018

High-depth whole genome sequencing of an Ashkenazi Jewish reference panel: enhancing sensitivity, accuracy, and imputation.

Hum Genet 2018 Apr 28;137(4):343-355. Epub 2018 Apr 28.

Department of Computer Science, Columbia University, 500 W 120th St, New York, NY, 10027, USA.

While increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. Here, we sequenced at full-depth (≥ 30×), across two platforms (Illumina X Ten and Complete Genomics, Inc.), a moderately large (n = 738) cohort of samples drawn from the Ashkenazi Jewish population. We developed a series of quality control steps to optimize sensitivity, specificity, and comprehensiveness of variant calls in the reference panel, and then tested the accuracy of imputation against target cohorts drawn from the same population. Quality control (QC) thresholds for the Illumina X Ten platform were identified that permitted highly accurate calling of single nucleotide variants across 94% of the genome. QC procedures also identified numerous regions that are poorly mapped using current reference or alternate assemblies. After stringent QC, the population-specific reference panel produced more accurate and comprehensive imputation results relative to publicly available, large cosmopolitan reference panels, especially in the range of rare variants that may be most critical to further progress in mapping of complex phenotypes. The population-specific reference panel also permitted enhanced filtering of clinically irrelevant variants from personal genomes.
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http://dx.doi.org/10.1007/s00439-018-1886-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954822PMC
April 2018

The time and place of European admixture in Ashkenazi Jewish history.

PLoS Genet 2017 04 4;13(4):e1006644. Epub 2017 Apr 4.

Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel.

The Ashkenazi Jewish (AJ) population is important in genetics due to its high rate of Mendelian disorders. AJ appeared in Europe in the 10th century, and their ancestry is thought to comprise European (EU) and Middle-Eastern (ME) components. However, both the time and place of admixture are subject to debate. Here, we attempt to characterize the AJ admixture history using a careful application of new and existing methods on a large AJ sample. Our main approach was based on local ancestry inference, in which we first classified each AJ genomic segment as EU or ME, and then compared allele frequencies along the EU segments to those of different EU populations. The contribution of each EU source was also estimated using GLOBETROTTER and haplotype sharing. The time of admixture was inferred based on multiple statistics, including ME segment lengths, the total EU ancestry per chromosome, and the correlation of ancestries along the chromosome. The major source of EU ancestry in AJ was found to be Southern Europe (≈60-80% of EU ancestry), with the rest being likely Eastern European. The inferred admixture time was ≈30 generations ago, but multiple lines of evidence suggest that it represents an average over two or more events, pre- and post-dating the founder event experienced by AJ in late medieval times. The time of the pre-bottleneck admixture event, which was likely Southern European, was estimated to ≈25-50 generations ago.
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http://dx.doi.org/10.1371/journal.pgen.1006644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380316PMC
April 2017

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

Nat Genet 2017 01 21;49(1):27-35. Epub 2016 Nov 21.

Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
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http://dx.doi.org/10.1038/ng.3725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737772PMC
January 2017

A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF.

Gastroenterology 2016 10 1;151(4):710-723.e2. Epub 2016 Jul 1.

Department of Medicine, New York University School of Medicine, New York, New York.

Background & Aims: Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects.

Methods: We performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony-stimulating factor 2-receptor β common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and granulocyte-macrophage colony-stimulating factor-responsive cells were defined by adenomatous polyposis coli (APC) time-of-flight mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and the expression and functions of gene products were compared.

Results: In the discovery cohort, we associated CD with a frameshift mutation in CSF2RB (P = 8.52 × 10(-4)); the finding was validated in the replication cohort (combined P = 3.42 × 10(-6)). Incubation of intestinal lamina propria leukocytes with granulocyte-macrophage colony-stimulating factor resulted in high levels of phosphorylation of signal transducer and activator of transcription (STAT5) and lesser increases in phosphorylation of extracellular signal-regulated kinase and AK straining transforming (AKT). Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 after stimulation with granulocyte-macrophage colony-stimulating factor, compared with cells transfected with control CSF2RB, indicating a dominant-negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) had reduced responses to granulocyte-macrophage colony-stimulating factor and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance.

Conclusions: In a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB. Intestinal monocytes from carriers of this mutation had reduced responses to granulocyte-macrophage colony-stimulating factor, providing an additional mechanism for alterations to the innate immune response in individuals with CD.
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http://dx.doi.org/10.1053/j.gastro.2016.06.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037012PMC
October 2016

Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women.

JAMA Psychiatry 2016 05;73(5):497-505

CIBERSAM, University Hospital Marqués de Valdecilla, University of Cantabria-IDIVAL, Department of Psychiatry, Santander, Spain28 Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain.

Importance: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age.

Objective: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets.

Design, Setting, And Participants: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study.

Main Outcomes And Measures: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age.

Results: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014.

Conclusions And Relevance: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.
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http://dx.doi.org/10.1001/jamapsychiatry.2016.0129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785705PMC
May 2016

Expanded genetic screening panel for the Ashkenazi Jewish population.

Genet Med 2016 05 3;18(5):522-8. Epub 2015 Sep 3.

Department of Pathology, Montefiore Medical Center, New York, New York, USA.

Purpose: Carrier screening programs that identify the presence of known mutations have been effective for reducing the incidence of autosomal recessive conditions in the Ashkenazi Jewish (AJ) population and other populations. Yet, these programs have not realized their full potential. Furthermore, many known autosomal recessive and dominant conditions are not screened for and the molecular basis of other conditions for which screening might be offered is unknown.

Methods: Through literature review and annotation of full sequenced genomes from healthy individuals, we expanded the list of mutations. Mutations were identified in a sample of 128 fully sequenced AJ genomes that were filtered through clinical databases and curated manually for clinical validity and utility using the American College of Medical Genetics and Genomics scoring (ACMG) system. Other known mutations were identified through literature review.

Results: A panel of 163 mutations was identified for 76 autosomal recessive, 24 autosomal dominant, and 3 X-linked disorders.

Conclusion: Screening for a broader range of disorders not only could further reduce the incidence of autosomal recessive disorders but also could offer the benefits of early or presymptomatic diagnosis.Genet Med 18 5, 522-528.
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http://dx.doi.org/10.1038/gim.2015.123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814352PMC
May 2016

Genome-wide association study of schizophrenia in Ashkenazi Jews.

Am J Med Genet B Neuropsychiatr Genet 2015 Dec 21;168(8):649-59. Epub 2015 Jul 21.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Schizophrenia is a common, clinically heterogeneous disorder associated with lifelong morbidity and early mortality. Several genetic variants associated with schizophrenia have been identified, but the majority of the heritability remains unknown. In this study, we report on a case-control sample of Ashkenazi Jews (AJ), a founder population that may provide additional insights into genetic etiology of schizophrenia. We performed a genome-wide association analysis (GWAS) of 592 cases and 505 controls of AJ ancestry ascertained in the US. Subsequently, we performed a meta-analysis with an Israeli AJ sample of 913 cases and 1640 controls, followed by a meta-analysis and polygenic risk scoring using summary results from Psychiatric GWAS Consortium 2 schizophrenia study. The U.S. AJ sample showed strong evidence of polygenic inheritance (pseudo-R(2) ∼9.7%) and a SNP-heritability estimate of 0.39 (P = 0.00046). We found no genome-wide significant associations in the U.S. sample or in the combined US/Israeli AJ meta-analysis of 1505 cases and 2145 controls. The strongest AJ specific associations (P-values in 10(-6) -10(-7) range) were in the 22q 11.2 deletion region and included the genes TBX1, GLN1, and COMT. Supportive evidence (meta P < 1 × 10(-4) ) was also found for several previously identified genome-wide significant findings, including the HLA region, CNTN4, IMMP2L, and GRIN2A. The meta-analysis of the U.S. sample with the PGC2 results provided initial genome-wide significant evidence for six new loci. Among the novel potential susceptibility genes is PEPD, a gene involved in proline metabolism, which is associated with a Mendelian disorder characterized by developmental delay and cognitive deficits.
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http://dx.doi.org/10.1002/ajmg.b.32349DOI Listing
December 2015

Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment.

Am J Med Genet B Neuropsychiatr Genet 2015 Jul 7;168B(5):363-73. Epub 2015 May 7.

Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, United Kingdom.

Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10(-4) ) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10(-7) ), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10(-9) ). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness.
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http://dx.doi.org/10.1002/ajmg.b.32319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500051PMC
July 2015

Common variants of IRF3 conferring risk of schizophrenia.

J Psychiatr Res 2015 May 20;64:67-73. Epub 2015 Mar 20.

Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China; CAS Center for Excellence in Brain Science, Chinese Academy of Sciences, Shanghai, China. Electronic address:

Schizophrenia is a brain disorder with high heritability. Recent studies have implicated genes involved in the immune response pathway in the pathogenesis of schizophrenia. Interferon regulatory factor 3 (IRF3), a virus-immune-related gene, activates the transcription of several interferon-induced genes, and functionally interacts with several schizophrenia susceptibility genes. To test whether IRF3 is a schizophrenia susceptibility gene, we analyzed the associations of its SNPs with schizophrenia in independent population samples as well as reported data from expression quantitative trait loci (eQTL) in healthy individuals. We observed multiple independent SNPs in IRF3 showing nominally significant associations with schizophrenia (P < 0.05); more intriguingly, a SNP (rs11880923), which is significantly correlated with IRF3 expression in independent samples (P < 0.05), is also consistently associated with schizophrenia across different cohorts and in combined samples (odds ratio = 1.075, Pmeta = 2.08 × 10(-5)), especially in Caucasians (odds ratio = 1.078, Pmeta = 2.46 × 10(-5)). These results suggested that IRF3 is likely a risk gene for schizophrenia, at least in Caucasians. Although the clinical associations of IRF3 with diagnosis did not achieve genome-wide level of statistical significance, the observed odds ratio is comparable with other susceptibility loci identified through large-scale genetic association studies on schizophrenia, which could be regarded simply as small but detectable effects.
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http://dx.doi.org/10.1016/j.jpsychires.2015.03.008DOI Listing
May 2015

SNP-microarrays can accurately identify the presence of an individual in complex forensic DNA mixtures.

Forensic Sci Int Genet 2015 May 29;16:208-215. Epub 2015 Jan 29.

Department of Genetics, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Electronic address:

Common forensic and mass disaster scenarios present DNA evidence that comprises a mixture of several contributors. Identifying the presence of an individual in such mixtures has proven difficult. In the current study, we evaluate the practical usefulness of currently available "off-the-shelf" SNP microarrays for such purposes. We found that a set of 3000 SNPs specifically selected for this purpose can accurately identify the presence of an individual in complex DNA mixtures of various compositions. For example, individuals contributing as little as 5% to a complex DNA mixture can be robustly identified even if the starting DNA amount was as little as 5.0ng and had undergone whole-genome amplification (WGA) prior to SNP analysis. The work presented in this study represents proof-of-principle that our previously proposed approach, can work with real "forensic-type" samples. Furthermore, in the absence of a low-density focused forensic SNP microarray, the use of standard, currently available high-density SNP microarrays can be similarly used and even increase statistical power due to the larger amount of available information.
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http://dx.doi.org/10.1016/j.fsigen.2015.01.009DOI Listing
May 2015

Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins.

Nat Commun 2014 Sep 9;5:4835. Epub 2014 Sep 9.

1] Department of Pathology and Cell Biology, Columbia University Medical Center, 1150 St Nicholas Avenue, New York, New York 10032, USA [2] Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 1150 St Nicholas Avenue, New York, New York 10032, USA.

The Ashkenazi Jewish (AJ) population is a genetic isolate close to European and Middle Eastern groups, with genetic diversity patterns conducive to disease mapping. Here we report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes. Our panel improves imputation accuracy for AJ SNP arrays by 28%, and covers at least one haplotype in ≈ 67% of any AJ genome with long, identical-by-descent segments. Reconstruction of recent AJ history from such segments confirms a recent bottleneck of merely ≈ 350 individuals. Modelling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an even admixture of European and likely Middle Eastern origins. We date the split between the two ancestral populations to ≈ 12-25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum.
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http://dx.doi.org/10.1038/ncomms5835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164776PMC
September 2014

Excess of homozygosity in the major histocompatibility complex in schizophrenia.

Hum Mol Genet 2014 Nov 18;23(22):6088-95. Epub 2014 Jun 18.

The Zucker Hillside Hospital, Psychiatry Research, 75-59 263rd Street, Glen Oaks, NY 11004, USA, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA, Hofstra University School of Medicine, 500 Hofstra University, Hempstead, NY 11549, USA,

Genome-wide association studies (GWAS) in schizophrenia have focused on additive allelic effects to identify disease risk loci. In order to examine potential recessive effects, we applied a novel approach to identify regions of excess homozygosity in an ethnically homogenous cohort: 904 schizophrenia cases and 1640 controls drawn from the Ashkenazi Jewish (AJ) population. Genome-wide examination of runs of homozygosity identified an excess in cases localized to the major histocompatibility complex (MHC). To refine this signal, we used the recently developed GERMLINE algorithm to identify chromosomal segments shared identical-by-descent (IBD) and compared homozygosity at such segments in cases and controls. We found a significant excess of homozygosity in schizophrenia cases compared with controls in the MHC (P-value = 0.003). An independent replication cohort of 548 schizophrenia cases from Japan and 542 matched healthy controls demonstrated similar effects. The strongest case-control recessive effects (P = 8.81 × 10(-8)) were localized to a 53-kb region near HLA-A, in a segment encompassing three poorly annotated genes, TRIM10, TRIM15 and TRIM40. At the same time, an adjacent segment in the Class I MHC demonstrated clear additive effects on schizophrenia risk, demonstrating the complexity of association in the MHC and the ability of our IBD approach to refine localization of broad signals derived from conventional GWAS. In sum, homozygosity in the classical MHC region appears to convey significant risk for schizophrenia, consistent with the ecological literature suggesting that homozygosity at the MHC locus may be associated with vulnerability to disease.
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http://dx.doi.org/10.1093/hmg/ddu308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204767PMC
November 2014

Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes.

Hum Mol Genet 2014 Sep 19;23(17):4693-702. Epub 2014 May 19.

Genetic Institute and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts.
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http://dx.doi.org/10.1093/hmg/ddu158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119402PMC
September 2014

Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder.

Nat Commun 2013 ;4:2739

1] Division of Research, Department of Psychiatry, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, New York 11004, USA [2] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA [3] Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA [4] Department of Psychiatry, Hofstra University School of Medicine, Hempstead, New York 11550, USA [5] Department of Molecular Medicine, Hofstra University School of Medicine, Hempstead, New York 11550, USA [6].

Schizophrenia and bipolar disorder are major psychiatric disorders with high heritability and overlapping genetic variance. Here we perform a genome-wide association study in an ethnically homogeneous cohort of 904 schizophrenia cases and 1,640 controls drawn from the Ashkenazi Jewish population. We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in Pmeta=9.49 × 10(-12) (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.08-1.17) across both disorders and Pmeta=2.67 × 10(-8) (OR=1.15, 95% CI: 1.08-1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders.
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http://dx.doi.org/10.1038/ncomms3739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905728PMC
June 2014

Implication of a rare deletion at distal 16p11.2 in schizophrenia.

JAMA Psychiatry 2013 Mar;70(3):253-60

Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, New York 11004, USA.

Context: Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication.

Objective: To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples.

Design: Genetic association study of microarray data.

Setting: Samples of DNA were collected at 9 sites from different countries.

Participants: Two discovery cohorts consisted of 790 cases with schizophrenia and schizoaffective disorder and 1347 controls of Ashkenazi Jewish descent and 662 parent-offspring trios from Bulgaria, of which the offspring had schizophrenia or schizoaffective disorder. Replication data sets consisted of 12,398 cases and 17,945 controls.

Main Outcome Measures: Statistically increased rate of specific copy number variations in cases vs controls.

Results: One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 of 13,850 cases (0.094%) and 3 of 19,954 controls (0.015%) (odds ratio, 6.25 [95% CI, 1.78-21.93]; P = .001, Fisher exact test).

Conclusions: Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains 9 genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional 8 genes. Our findings add a new locus to the list of copy number variations that increase the risk for development of schizophrenia.
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http://dx.doi.org/10.1001/2013.jamapsychiatry.71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750982PMC
March 2013

The variance of identity-by-descent sharing in the Wright-Fisher model.

Genetics 2013 Mar 24;193(3):911-28. Epub 2012 Dec 24.

Department of Computer Science, Columbia University, New York, NY 10027, USA.

Widespread sharing of long, identical-by-descent (IBD) genetic segments is a hallmark of populations that have experienced recent genetic drift. Detection of these IBD segments has recently become feasible, enabling a wide range of applications from phasing and imputation to demographic inference. Here, we study the distribution of IBD sharing in the Wright-Fisher model. Specifically, using coalescent theory, we calculate the variance of the total sharing between random pairs of individuals. We then investigate the cohort-averaged sharing: the average total sharing between one individual and the rest of the cohort. We find that for large cohorts, the cohort-averaged sharing is distributed approximately normally. Surprisingly, the variance of this distribution does not vanish even for large cohorts, implying the existence of "hypersharing" individuals. The presence of such individuals has consequences for the design of sequencing studies, since, if they are selected for whole-genome sequencing, a larger fraction of the cohort can be subsequently imputed. We calculate the expected gain in power of imputation by IBD and subsequently in power to detect an association, when individuals are either randomly selected or specifically chosen to be the hypersharing individuals. Using our framework, we also compute the variance of an estimator of the population size that is based on the mean IBD sharing and the variance in the sharing between inbred siblings. Finally, we study IBD sharing in an admixture pulse model and show that in the Ashkenazi Jewish population the admixture fraction is correlated with the cohort-averaged sharing.
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http://dx.doi.org/10.1534/genetics.112.147215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584006PMC
March 2013

Length distributions of identity by descent reveal fine-scale demographic history.

Am J Hum Genet 2012 Nov 25;91(5):809-22. Epub 2012 Oct 25.

Department of Computer Science, Columbia University, New York, NY 10027, USA.

Data-driven studies of identity by descent (IBD) were recently enabled by high-resolution genomic data from large cohorts and scalable algorithms for IBD detection. Yet, haplotype sharing currently represents an underutilized source of information for population-genetics research. We present analytical results on the relationship between haplotype sharing across purportedly unrelated individuals and a population's demographic history. We express the distribution of IBD sharing across pairs of individuals for segments of arbitrary length as a function of the population's demography, and we derive an inference procedure to reconstruct such demographic history. The accuracy of the proposed reconstruction methodology was extensively tested on simulated data. We applied this methodology to two densely typed data sets: 500 Ashkenazi Jewish (AJ) individuals and 56 Kenyan Maasai (MKK) individuals (HapMap 3 data set). Reconstructing the demographic history of the AJ cohort, we recovered two subsequent population expansions, separated by a severe founder event, consistent with previous analysis of lower-throughput genetic data and historical accounts of AJ history. In the MKK cohort, high levels of cryptic relatedness were detected. The spectrum of IBD sharing is consistent with a demographic model in which several small-sized demes intermix through high migration rates and result in enrichment of shared long-range haplotypes. This scenario of historically structured demographies might explain the unexpected abundance of runs of homozygosity within several populations.
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http://dx.doi.org/10.1016/j.ajhg.2012.08.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487132PMC
November 2012

Population-specific association between a polymorphic variant in ST18, encoding a pro-apoptotic molecule, and pemphigus vulgaris.

J Invest Dermatol 2012 Jul 22;132(7):1798-805. Epub 2012 Mar 22.

Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease caused by anti-epithelial antibodies, leading to disruption of cell-cell adhesion. Although the disease is exceedingly rare worldwide, it is known to be relatively prevalent in Jewish populations. The low prevalence of the disease represents a significant obstacle to a genome-wide approach to the mapping of susceptibility genes. We reasoned that the study of a genetically homogeneous cohort characterized by a high prevalence of PV may help exposing associated signals while reducing spurious results due to population sub-structure. We performed a genome-wide association study using 300K single-nucleotide polymorphisms (SNPs) in a case-control study of 100 PV patients of Jewish descent and 397 matched control individuals, followed by replication of significantly associated SNPs in three additional cohorts of Jewish, Egyptian, and German origin. In addition to the major histocompatibility complex locus, a genomic segment on 8q11.23 that spans the ST18 gene was also found to be significantly associated with PV. This association was confirmed in the Jewish and Egyptian replication sets but not in the German sample, suggesting that ST18-associated variants may predispose to PV in a population-specific manner. ST18 regulates apoptosis and inflammation, two processes of direct relevance to the pathogenesis of PV. Further supporting the relevance of ST18 to PV, we found this gene to be overexpressed in the skin of PV patients as compared with healthy individuals.
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http://dx.doi.org/10.1038/jid.2012.46DOI Listing
July 2012

A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci.

PLoS Genet 2012 8;8(3):e1002559. Epub 2012 Mar 8.

Department of Computer Sciences, Columbia University, New York, New York, United States of America.

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻⁶). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻⁸; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻⁹; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻⁸; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻⁸; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻⁹; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.
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http://dx.doi.org/10.1371/journal.pgen.1002559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297573PMC
September 2012

Implications for health and disease in the genetic signature of the Ashkenazi Jewish population.

Genome Biol 2012 Jan 25;13(1):R2. Epub 2012 Jan 25.

Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of the North Shore - Long Island Jewish Health System, 75-59, 263rd St Glen Oaks, NY 11004, USA.

Background: Relatively small, reproductively isolated populations with reduced genetic diversity may have advantages for genomewide association mapping in disease genetics. The Ashkenazi Jewish population represents a unique population for study based on its recent (< 1,000 year) history of a limited number of founders, population bottlenecks and tradition of marriage within the community. We genotyped more than 1,300 Ashkenazi Jewish healthy volunteers from the Hebrew University Genetic Resource with the Illumina HumanOmni1-Quad platform. Comparison of the genotyping data with that of neighboring European and Asian populations enabled the Ashkenazi Jewish-specific component of the variance to be characterized with respect to disease-relevant alleles and pathways.

Results: Using clustering, principal components, and pairwise genetic distance as converging approaches, we identified an Ashkenazi Jewish-specific genetic signature that differentiated these subjects from both European and Middle Eastern samples. Most notably, gene ontology analysis of the Ashkenazi Jewish genetic signature revealed an enrichment of genes functioning in transepithelial chloride transport, such as CFTR, and in equilibrioception, potentially shedding light on cystic fibrosis, Usher syndrome and other diseases over-represented in the Ashkenazi Jewish population. Results also impact risk profiles for autoimmune and metabolic disorders in this population. Finally, residual intra-Ashkenazi population structure was minimal, primarily determined by class 1 MHC alleles, and not related to host country of origin.

Conclusions: The Ashkenazi Jewish population is of potential utility in disease-mapping studies due to its relative homogeneity and distinct genomic signature. Results suggest that Ashkenazi-associated disease genes may be components of population-specific genomic differences in key functional pathways.
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http://dx.doi.org/10.1186/gb-2012-13-1-r2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334583PMC
January 2012

The architecture of long-range haplotypes shared within and across populations.

Mol Biol Evol 2012 Feb 6;29(2):473-86. Epub 2011 Oct 6.

Department of Computer Science, Columbia University, New York, New York, USA.

Homologous long segments along the genomes of close or remote relatives that are identical by descent (IBD) from a common ancestor provide clues for recent events in human genetics. We set out to extensively map such IBD segments in large cohorts and investigate their distribution within and across different populations. We report analysis of several data sets, demonstrating that IBD is more common than expected by naïve models of population genetics. We show that the frequency of IBD pairs is population dependent and can be used to cluster individuals into populations, detect a homogeneous subpopulation within a larger cohort, and infer bottleneck events in such a subpopulation. Specifically, we show that Ashkenazi Jewish individuals are all connected through transitive remote family ties evident by sharing of 50 cM IBD to a publicly available data set of less than 400 individuals. We further expose regions where long-range haplotypes are shared significantly more often than elsewhere in the genome, observed across multiple populations, and enriched for common long structural variation. These are inconsistent with recent relatedness and suggest ancient common ancestry, with limited recombination between haplotypes.
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http://dx.doi.org/10.1093/molbev/msr133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350316PMC
February 2012

Forensic identification of an individual in complex DNA mixtures.

Forensic Sci Int Genet 2011 Nov 2;5(5):428-35. Epub 2010 Oct 2.

Department of Genetics, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel.

The identification of a suspect in a complex DNA mixture typed with standard short tandem repeat (STR) kits has proved difficult. In the current study we present the theoretical framework of a method aimed to resolve this problem in forensic cases. The method suggests genotyping a specially designed panel of 1000-3000 single nucleotide polymorphisms (SNPs), each with a relatively low (<0.1) minor allele frequency (MAF). The rationale of this method is that any individual will carry a specific set of dozens of rare alleles and the complex DNA mixture will carry this particular set only if the one individual is represented in the DNA mixture. The efficiency of the method is evaluated by estimating the probability that a random man will not be excluded (RMNE) from the mixture. When this probability, P(RMNE), is low, one can conclude that the suspect's DNA is present in the DNA mixture. Essentially, a P(RMNE)<10(-9) is considered as proof, whereas a P(RMNE)<10(-6) is considered strong evidence. For completeness, we also analyzed the method using the likelihood ratio (LR) approach. We have analyzed the method for a variety of conditions and found that generally the method will provide highly significant results even for complex mixtures combining up to 10 individuals. The method performs well even when close relatives (one or two brothers) are present in the complex DNA mixture and when contributors or suspects come from different populations. We have also found that the method can accurately identify the number of contributors to the mixture, something that in some instances has significant forensic value on its own.
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http://dx.doi.org/10.1016/j.fsigen.2010.09.002DOI Listing
November 2011

Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2.

Genome Res 2010 Sep 5;20(9):1180-90. Epub 2010 Aug 5.

Department of Genetics, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.

Chronic neuropathic pain is affected by specifics of the precipitating neural pathology, psychosocial factors, and by genetic predisposition. Little is known about the identity of predisposing genes. Using an integrative approach, we discovered that CACNG2 significantly affects susceptibility to chronic pain following nerve injury. CACNG2 encodes for stargazin, a protein intimately involved in the trafficking of glutamatergic AMPA receptors. The protein might also be a Ca(2+) channel subunit. CACNG2 has previously been implicated in epilepsy. Initially, using two fine-mapping strategies in a mouse model (recombinant progeny testing [RPT] and recombinant inbred segregation test [RIST]), we mapped a pain-related quantitative trait locus (QTL) (Pain1) into a 4.2-Mb interval on chromosome 15. This interval includes 155 genes. Subsequently, bioinformatics and whole-genome microarray expression analysis were used to narrow the list of candidates and ultimately to pinpoint Cacng2 as a likely candidate. Analysis of stargazer mice, a Cacng2 hypomorphic mutant, provided electrophysiological and behavioral evidence for the gene's functional role in pain processing. Finally, we showed that human CACNG2 polymorphisms are associated with chronic pain in a cohort of cancer patients who underwent breast surgery. Our findings provide novel information on the genetic basis of neuropathic pain and new insights into pain physiology that may ultimately enable better treatments.
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http://dx.doi.org/10.1101/gr.104976.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928496PMC
September 2010

Correlational analysis for identifying genes whose regulation contributes to chronic neuropathic pain.

Mol Pain 2009 Feb 19;5. Epub 2009 Feb 19.

Center for Oral Biology, Novum, Karolinska Institutet, S-141 04 Huddinge, Sweden.

Background: Nerve injury-triggered hyperexcitability in primary sensory neurons is considered a major source of chronic neuropathic pain. The hyperexcitability, in turn, is thought to be related to transcriptional switching in afferent cell somata. Analysis using expression microarrays has revealed that many genes are regulated in the dorsal root ganglion (DRG) following axotomy. But which contribute to pain phenotype versus other nerve injury-evoked processes such as nerve regeneration? Using the L5 spinal nerve ligation model of neuropathy we examined differential changes in gene expression in the L5 (and L4) DRGs in five mouse strains with contrasting susceptibility to neuropathic pain. We sought genes for which the degree of regulation correlates with strain-specific pain phenotype.

Results: In an initial experiment six candidate genes previously identified as important in pain physiology were selected for in situ hybridization to DRG sections. Among these, regulation of the Na+ channel alpha subunit Scn11a correlated with levels of spontaneous pain behavior, and regulation of the cool receptor Trpm8 correlated with heat hypersensibility. In a larger scale experiment, mRNA extracted from individual mouse DRGs was processed on Affymetrix whole-genome expression microarrays. Overall, 2552 +/- 477 transcripts were significantly regulated in the axotomized L5DRG 3 days postoperatively. However, in only a small fraction of these was the degree of regulation correlated with pain behavior across strains. Very few genes in the "uninjured" L4DRG showed altered expression (24 +/- 28).

Conclusion: Correlational analysis based on in situ hybridization provided evidence that differential regulation of Scn11a and Trpm8 contributes to across-strain variability in pain phenotype. This does not, of course, constitute evidence that the others are unrelated to pain. Correlational analysis based on microarray data yielded a larger "look-up table" of genes whose regulation likely contributes to pain variability. While this list is enriched in genes of potential importance for pain physiology, and is relatively free of the bias inherent in the candidate gene approach, additional steps are required to clarify which transcripts on the list are in fact of functional importance.
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http://dx.doi.org/10.1186/1744-8069-5-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649910PMC
February 2009

Association between golli-MBP and schizophrenia in the Jewish Ashkenazi population: are regulatory regions involved?

Int J Neuropsychopharmacol 2009 Aug 21;12(7):885-94. Epub 2009 Jan 21.

Department of Human Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Multiple studies have reported oligodendrocyte and myelin abnormalities, as well as dysregulation of their related genes, in brains of schizophrenia patients. One of these genes is the myelin-basic-protein (MBP) gene, which encodes two families of proteins: classic-MBPs and golli-MBPs. While the classic-MBPs are predominantly located in the myelin sheaths of the nervous system, the golli proteins are more widely expressed and are found in both the immune and the nervous systems. In the present study we performed a case-control association analysis of golli-MBP in two separate Jewish Ashkenazi cohorts (cohort I: 120 patients, 236 controls; cohort II: 379 patients, 380 controls). In addition we performed an expression analysis of golli-MBP mRNA in post-mortem dorsolateral prefrontal cortex samples of schizophrenia patients, and matched controls. In the first cohort we observed association between six (out of 26 genotyped) single nucleotide polymorphisms (SNPs) and the disease (p<0.05). Of these, three are from one linkage disequilibrium (LD) block which contains a CTCF binding region. Haplotype analysis revealed significant 'risk'/'protective' haplotypes (strongest p=0.005, each) for schizophrenia. The three SNPs (rs12458282, rs2008323, rs721286) were then genotyped in the second cohort. The combined results showed strong effects, both in the single marker and in haplotype analyses (strongest OR 1.77, p=0.0005; OR 1.61, p=0.00001, respectively). Sequencing the CTCF binding region revealed three SNPs in complete LD with the associated haplotypes, located in close proximity to the CTCF binding site. Expression analysis found no significant differences in golli-MBP mRNA levels. These findings suggest that golli-MBP is a possible susceptibility gene for schizophrenia.
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http://dx.doi.org/10.1017/S1461145708009887DOI Listing
August 2009

Identification of loci associated with schizophrenia by genome-wide association and follow-up.

Nat Genet 2008 Sep;40(9):1053-5

Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK.

We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10(-5) in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 x 10(-4)), and the overall pattern of replication was unlikely to occur by chance (P = 9 x 10(-8)). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 x 10(-7)) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 x 10(-9)).
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http://dx.doi.org/10.1038/ng.201DOI Listing
September 2008
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