Stacey Cherny | Tel Aviv University (original) (raw)

Papers by Stacey Cherny

Lupus, 2011

Objective: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex gen... more Objective: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. Methods: In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. ...

Osteoporosis International, 2020

The relationship between OA and osteoporosis characteristics remains controversial. This study re... more The relationship between OA and osteoporosis characteristics remains controversial. This study revealed that age-adjusted hand OA is associated with lower hand/arm BMD levels. Wrist fracture occurrence is associated with increased OA hand scores and low arm BMD. Conversely, age-adjusted knee and spine OA is associated with high spine, hip, and total BMDs. Osteoarthritis (OA) and osteoporosis are two common musculoskeletal diseases which contribute a high burden of disability, yet assessments of their relationship remains controversial. The aim of this study was to clarify the association between bone mineral densities (BMD) of the hand, arm, spine, hip, and total body, and OA of the hand and knee and lumbar disc degeneration in two different ethnic groups. Radiographic assessments of the hand, knee, and spine were collected and coded for joint space narrowing, osteophytes, and the Kellgren-Lawrence score from Chuvashian (n = 1504) and British (n = 2280) individuals. BMD measurements of standard skeletal sites were estimated by dual X-ray absorptiometry. Age- and familial-adjusted regression analyses were conducted to determine associations. Knee OA affection was positively associated with elevated hip, spine, and total body BMD levels (p < 0.001). Additionally, disc degeneration phenotypes showed significant positive associations with the hip, spine, and total BMD (p < 0.001). However, increased hand OA scores was significantly negatively correlated with arm and hand BMD measurements in males and females in both samples (p < 0.001). Additionally, higher hand OA scores were significantly associated with wrist fracture. We discovered a clear pattern of association between hand OA and low hand and arm BMD, with increased risk of wrist fracture, as well as reproducing previous associations between knee and spine OA and elevated spine, hip, and total body BMD. It appears that hand OA manifests differently in comparison to hip and knee OA.

Introduction: Schizophrenia (SC) is a complicated mental disorder characterized by abnormal perce... more Introduction: Schizophrenia (SC) is a complicated mental disorder characterized by abnormal perception, emotion, cognition, and so on. With the rapid development of brain image techniques, the relationship between the brain metabolites and the clinical manifestation of schizophrenia has become a popular perspective to explore the mechanism of SC. Magnetic resonance spectroscopy (MRS), a technique that exploits the magnetic properties of certain atomic nuclei, can reflect the concentration of brain metabolites, and thus reveal the activation and number of neuron cells in the brain cortex. The number of researches using MRS to explore the pathophysiology of SC has grown rapidly in recent years. Most studies have reported a decreased metabolite level in DLPFC among patients with SC, comparing to the healthy controls. Depletions of metabolite of NAA, Glx, Cho or MI in DLPFC of patients with SC has been widely detected by researchers, which are thought to reflect the dysfunction of schizophrenia-related neuron cells. However, few studies have explored whether the change in certain metabolite is correlated with the process of disease or its medical treatment. As a matter of fact, it is necessary to perform long-term longitudinal studies to explore the problem. Aims: This study aimed to investigate the correlation between the alterations in dorsolateral prefrontal cortex (DLPFC) metabolite level of patients with first-episode schizophrenia (FES) and the change in clinical symptoms after one year treatment. Methods: A total of 33 patients were recruited from the First Affiliated Hospital of Medical School of Zhejiang University, while 33 healthy people were recruited from communities or through advertisements. FES patients underwent 1H-MRS scan twice: one at the baseline and the other one year later, while the healthy group underwent it only once at the baseline. The symptom severity of patients was measured by PANSS. Differences in demographical characteristics and the index of 1H-MRS at the baseline between control and patient groups were determined using the independent t-test or χ2 test. The paired t-test (two-tailed) was used to evaluate significant changes in the index of 1H-MRS, neuropsychological assessment results, and clinical symptoms before and after an atypical antipsychotic treatment. Partial correlation analysis was used to calculate the correlations between the metabolite alteration and pathological characteristics or cognition condition (set baseline metabolite concentration as the unconcerned confounding factor). The level of significance was set at α = 0.05. Results: An increase in the NAA/Cr level was detected in the left DLPFC of patients with FES. The change in the NAA/Cr level was significantly correlated with the alteration in their PANSS-P score. The Cho/Cr levels on both sides of DLPFC in patients with FES were lower compared with the healthy controls both at the baseline and after the treatment. The NAA/Cr and MI/Cr levels in the right DLPFC decreased after the treatment. Conclusions: (1) the depletion of NAA in left DLPFC might be a state characteristic (2) the Cho/Cr level might be the potential endophenotype of schizophrenia (3) the decrease of NAA/Cr and MI/Cr level in right DLPFC might be due to the deterioration of schizophrenia. P.3.a.002 Polygenic risk profile score increases schizophrenia liability mostly through cognition pathways: mathematical causation models with polygenic risk

Neurology, Jan 29, 2017

To characterize, among European and Han Chinese populations, the genetic predictors of maculopapu... more To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. We report an association between a rare variant in the complement factor H-related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10-11; odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Ch...

Schizophrenia bulletin, 2014

Recent years have seen considerable progress in epidemiological and molecular genetic research in... more Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerg...

PLoS Genetics, 2012

Hirschsprung disease (HSCR) is a congenital disorder characterized by aganglionosis of the distal... more Hirschsprung disease (HSCR) is a congenital disorder characterized by aganglionosis of the distal intestine. To assess the contribution of copy number variants (CNVs) to HSCR, we analysed the data generated from our previous genome-wide association study on HSCR patients, whereby we identified NRG1 as a new HSCR susceptibility locus. Analysis of 129 Chinese patients and 331 ethnically matched controls showed that HSCR patients have a greater burden of rare CNVs (p = 1.50610 25), particularly for those encompassing genes (p = 5.00610 26). Our study identified 246 rare-genic CNVs exclusive to patients. Among those, we detected a NRG3 deletion (p = 1.64610 23). Subsequent follow-up (96 additional patients and 220 controls) on NRG3 revealed 9 deletions (combined p = 3.36610 25) and 2 de novo duplications among patients and two deletions among controls. Importantly, NRG3 is a paralog of NRG1. Stratification of patients by presence/ absence of HSCR-associated syndromes showed that while syndromic-HSCR patients carried significantly longer CNVs than the non-syndromic or controls (p = 1.50610 25), non-syndromic patients were enriched in CNV number when compared to controls (p = 4.00610 26) or the syndromic counterpart. Our results suggest a role for NRG3 in HSCR etiology and provide insights into the relative contribution of structural variants in both syndromic and non-syndromic HSCR. This would be the first genome-wide catalog of copy number variants identified in HSCR.

Journal of Human Genetics, 2007

The epidemiology of multiple sclerosis suggests that a complex interaction of genes and environme... more The epidemiology of multiple sclerosis suggests that a complex interaction of genes and environment contribute to susceptibility. To enrich for families with large genetic effects and to potentially reduce genetic heterogeneity, we screened a sample of 18,794 probands and identified forty families with four or more affected individuals. Within these 40 families, HLA DRB1*15 was present in 70% of affected individuals; the transmission disequilibrium test showed a significant excess in transmission of DRB1*15 alleles to affected individuals (47 transmitted, 19 untransmitted, v 2 = 11.9, p = 0.00057). A 10 cM genome scan was performed and analyzed for linkage under a parametric model with heterogeneity. No excess of significant sharing was observed (HLOD [ 3.3) in the parametric multipoint analysis. No region exceeded that for marker GATA8A05 with an HLOD = 1.11. Follow-up genotyping with 17 microsatellites revealed a significant two-point parametric HLOD = 3.99 at marker D4S1597. Transmission disequilibrium tests for markers in this candidate region showed no transmission distortion. A scan for variants in a gene adjacent to D4S1597, PALLD, was negative for synonymous or nonsynonymous changes. A final multipoint scan incorporating all microsatellites in the region provided an HLOD = 1.30. The inability to find significant linkage in these highly penetrant families suggests that linkage is not the optimal tool for dissecting the inheritance of MS.

BMC Genomics, 2008

Background: Large scale genome-wide association studies have become popular since the introductio... more Background: Large scale genome-wide association studies have become popular since the introduction of high throughput genotyping platforms. Efficient management of the vast array of data generated poses many challenges. Description: We have developed an open source web-based data management system for the large amount of genotype data generated from the Affymetrix GeneChip ® Mapping Array and Affymetrix Genome-Wide Human SNP Array platforms. The database supports genotype calling using DM, BRLMM, BRLMM-P or Birdseed algorithms provided by the Affymetrix Power Tools. The genotype and corresponding pedigree data are stored in a relational database for efficient downstream data manipulation and analysis, such as calculation of allele and genotype frequencies, sample identity checking, and export of genotype data in various file formats for analysis using commonly-available software. A novel method for genotyping error estimation is implemented using linkage disequilibrium information from the HapMap project. All functionalities are accessible via a web-based user interface. Conclusion: OpenADAM provides an open source database system for management of Affymetrix genome-wide association SNP data.

The American Journal of Human Genetics, 1999

American Journal of Medical Genetics, 2001

The American Journal of Human Genetics, 2010

Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of f... more Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG1) gene was associated with high BMD (p ¼ 5.27 3 10 À8 for lumbar spine [LS] and p ¼ 4.15 3 10 À5 for femoral neck [FN], n ¼ 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p ¼ 0.009, OR ¼ 0.7, 95% CI 0.57-0.93, n ¼ 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (p ¼ 8.52 3 10 À9 for LS and 3.47 3 10 À5 at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the ''G'' but not ''A'' allele of rs2273061. A mRNA expression study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG1 gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis.

Twin Research and Human Genetics

Dr Nick Martin has made enormous contributions to the field of behavior genetics over the past 50... more Dr Nick Martin has made enormous contributions to the field of behavior genetics over the past 50 years. Of his many seminal papers that have had a profound impact, we focus on his early work on the power of twin studies. He was among the first to recognize the importance of sample size calculation before conducting a study to ensure sufficient power to detect the effects of interest. The elegant approach he developed, based on the noncentral chi-squared distribution, has been adopted by subsequent researchers for other genetic study designs, and today remains a standard tool for power calculations in structural equation modeling and other areas of statistical analysis. The present brief article discusses the main aspects of his seminal paper, and how it led to subsequent developments, by him and others, as the field of behavior genetics evolved into the present era.

PLOS ONE

Bone mineral density (BMD) and lipid levels are two of the most extensively studied risk factors ... more Bone mineral density (BMD) and lipid levels are two of the most extensively studied risk factors for common diseases of aging, such as cardiovascular disease (CVD) and osteoporosis (OP). These two risk factors are also correlated with each other, but little is known about the molecular mechanisms behind this correlation. Recent studies revealed that circulating levels of several metabolites involved in the biosynthesis of androsterone correlate significantly with BMD and have the capacity to affect cholesterol and lipids levels. A main aim of the present study was to investigate the hypothesis that androsterone-related metabolites could provide a link between CVD and OP, as a common cause of lipid levels and BMD. The present study employed data from the NIHR BRC TwinsUK BioResource, comprising 1909 and 1994 monozygotic and dizygotic twin pairs, respectively, to address the causal relationships among BMD and lipids, and their associated metabolites, using reciprocal causation twin modelling, as well as Mendelian randomization (MR) using large publicly-available GWAS datasets on lipids and BMD, in conjunction with TwinsUK metabolite data. While results involving the twin modelling and MR analyses with metabolites were unable to establish a causal link between metabolite levels and either lipids or BMD, MR analyses of BMD and lipids suggest that lipid levels have a causal impact on BMD, which is consistent with findings from clinical trials of lipid-lowering drugs, which have also increased BMD.

Human genetics, 2018

Recently, the American College of Medical Genetics (ACMG) recommended the return of actionable se... more Recently, the American College of Medical Genetics (ACMG) recommended the return of actionable secondary findings detected from clinical sequencing. The reported frequency of secondary findings in Asian populations were highly variable and it is unclear whether the uniformity in coverage offered by whole-genome sequencing (WGS) may impact the estimate. In this analysis, we aimed to refine the rate of secondary findings on East Asians through a large-scale WGS study. We classified 1256 protein-altering or splicing variants of the 59 actionable genes detected from WGS of 954 East Asians in strict accordance with the ACMG and the Association for Molecular Pathology guidelines. A total of 21 pathogenic or likely pathogenic variants were detected in 24 of the 954 East Asian genomes with an estimate of 2.5% of East Asians carrying actionable variants. Although the overall estimate of secondary findings was consistent with those reported for non-East Asian ethnicities, genetic and allelic ...

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2018

Epilepsy and schizophrenia are common and typical neurological or mental illness respectively, an... more Epilepsy and schizophrenia are common and typical neurological or mental illness respectively, and sometimes they comorbid in the same patients, however the underlying genetic relationship between the two brain diseases is still not fully understood. To investigate the possible genetic contribution to their comorbidity, we performed polygenic risk score (PRS) analyses and genetic correlation estimation so as to identify the overall genetic overlap between the two diseases. The global schizophrenia PRS is strongly associated with schizophrenia phenotype in Hong Kong population (odds ratio = 1.7, p = 2.26E-16), and focal epilepsy PRS is moderately associated with epilepsy phenotype in Hong Kong population (odds ratio = 1.14, p = 0.013). However the disease-specific PRS can only predict its own well-matched phenotype but not the other ones (p > 0.05). This pattern is further supported by non-significant pairwise genetic correlation and insufficient statistical power for PRS associat...

European journal of human genetics : EJHG, Jun 1, 2018

Hirschsprung disease (HSCR) is a complex birth defect characterized by the lack of ganglion cells... more Hirschsprung disease (HSCR) is a complex birth defect characterized by the lack of ganglion cells along a variable length of the distal intestine. A large proportion of HSCR patients remain genetically unexplained. We applied whole-genome sequencing (WGS) on 9 trios where the probands are sporadically affected with the most severe form of the disorder and harbor no coding sequence variants affecting the function of known HSCR genes. We found de novo protein-altering variants in three intolerant to change genes-CCT2, VASH1, and CYP26A1-for which a plausible link with the enteric nervous system (ENS) exists. De novo single-nucleotide and indel variants were present in introns and non-coding neighboring regions of ENS-related genes, including NRG1 and ERBB4. Joint analysis with those inherited rare variants found under recessive and/or digenic models revealed both patient-unique and shared genetic features where rare variants were found to be enriched in the extracellular matrix-recept...

Human molecular genetics, Jan 21, 2017

The cloaca is an embryonic cavity that is divided into the urogenital sinus and rectum upon diffe... more The cloaca is an embryonic cavity that is divided into the urogenital sinus and rectum upon differentiation of the cloacal epithelium triggered by tissue-specific transcription factors including CDX2. Defective differentiation leads to persistent cloaca in humans (PC), a phenotype recapitulated in Cdx2 mutant mice. PC is linked to hypo/hyper-vitaminosis A. Although no gene has ever been identified, there is a strong evidence for a genetic contribution to PC. We applied whole-exome sequencing and copy-number-variants analyses to 21 PC patients and their unaffected parents.The damaging p.Cys132* and p.Arg237Hisde novo CDX2 variants were identified in two patients. These variants altered the expression of CYP26A1, a direct CDX2 target encoding the major retinoic acid (RA)-degrading enzyme. Other RA genes, including the RA-receptor alpha, were also mutated. Genes governing the development of cloaca-derived structures were recurrently mutated and over-represented in the basement-membrane...

Genetics

Evidence from genome-wide association studies (GWAS) suggest that pleiotropic effects on human co... more Evidence from genome-wide association studies (GWAS) suggest that pleiotropic effects on human complex phenotypes are very common. Recently, an atlas of genetic correlations among complex phenotypes has broadened our understanding of human diseases and traits. Here, we examine genetic overlap, from a gene-centric perspective, among the same 24 phenotypes previously investigated for genetic correlations. After adopting the multilevel pipeline (freely available at http://grass.cgs.hku.hk/limx/kgg/), which includes intragenic single nucleotide polymorphisms (SNPs), genes, and gene-sets, to estimate genetic similarities across phenotypes, a large amount of sharing of several biologically related phenotypes was confirmed. In addition, significant genetic overlaps were also found among phenotype pairs that were previously unidentified by SNP-level approaches. All these pairs with new genetic links are supported by earlier epidemiological evidence, although only a few of them have pleiotropic genes in the GWAS Catalog. Hence, our gene and gene-set analyses are able to provide new insights into cross-phenotype connections. The investigation on genetic sharing at three different levels presents a complementary picture of how common DNA sequence variations contribute to disease comorbidities and trait manifestations.

BMC medical genomics, Apr 17, 2017

Biliary Atresia (BA) is rare and genetically complex, and the pathogenesis is elusive. The diseas... more Biliary Atresia (BA) is rare and genetically complex, and the pathogenesis is elusive. The disease course is variable and can represent heterogeneity, which hinders effective disease management. Deciphering the BA phenotypic variance is a priority in clinics and can be achieved by the integrative analysis of genotype and phenotype. We aim to explore the BA phenotypic features and to delineate the source of its variance. The study is a cross-sectional observational study collating with case/control association analysis. One-hundred-and-eighty-one type III non-syndromic BA patients and 431 controls were included for case-control association tests, including 89 patients (47.19% males, born June 15th, 1981 to September 17th, 2007) have detailed clinical records with follow-up of the disease course (median ~17.2 years). BA-association genes from the genome-wide gene-based association test on common genetic variants (CV) and rare copy-number-variants (CNVs) from the genome-wide survey, th...