Differences in the connectivity of large-scale functional brain networks among individuals with a... more Differences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), derived from a recent GWAS of DSM-IV Alcohol Dependence (AD) conducted by the Psychiatric Genomics Consortium, relate to longitudinal measures of interhemispheric and intrahemispheric EEG connectivity (alpha, theta, and beta frequencies) in adolescent and young adult offspring from the Collaborative Study on the Genetics of Alcoholism (COGA) assessed between ages 12 and 31. Our findings indicate that AD PRS (p-threshold < 0.001) was associated with increased fronto-central, tempo-parietal, centro-parietal, and parietal-occipital interhemispheric theta and alpha connectivity in males only from ages 18–31 (beta coefficients ranged from 0.02–0.06, p-values ranged from 10−6–10−12), but not i...
Pathogenic allele frequency, carrier rate and affected rate were calculated and estimated based o... more Pathogenic allele frequency, carrier rate and affected rate were calculated and estimated based on Hardy-Weinberg equilibrium. RESULTS: In 1KG, non-related healthy individuals (n¼2504) carry SLC3A1 and SLC7A9 variants in 1705 and 1287 loci, respectively. In HGMD, there are 110 pathogenic SLC3A1 mutations, and 85 for SLC7A9. These variants include missense mutations, nonsense mutations, insertions, deletions, and complex substitutions. Among 2504 non-related, healthy individuals in 1KG, there are 26 people who carry 9 different SLC3A1 mutations, while 12 people carry 5 different SLC7A9 mutations. There were no homozygotes, compound heterozygotes, multiple variants in cis or trans, double homozygotes, or double heterozygotes. Therefore, disease-causing alleles have a frequency of 0.52% for SLC3A1, and 0.24% for SLC7A9.Type A cysteine stone has a carrier rate of 1 in 96 individuals and affected rate of 1 in 37,100 individuals. For type B, carrier and affected rates would be 1 in 209 and 1 in 174,167, respectively. The combined (type A + type B) carrier rate for cysteine stones is 1 in 66, with an overall affected rate of 1 in 30,585. CONCLUSIONS: The prevalence of cystine stone type A and type B estimated from a genetic approach is lower than the prevalence of observed of phenotypes (1 in 30,585 v.s. 1 in 7,000). Possible explanations include undiscovered mutations, undiscovered genes, a different inheritance model, selection advantages over the pathogenic variant, or founder effect. Further studies and investigations are required.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2020
African Americans (AA) have lower prevalence of alcohol dependence and higher subjective response... more African Americans (AA) have lower prevalence of alcohol dependence and higher subjective response to alcohol than European Americans. Genome-wide association studies (GWAS) have identified genes/variants associated with alcohol dependence specifically in AA; however, the sample sizes are still not large enough to detect variants with small effects. Admixture mapping is an alternative way to identify alcohol dependence genes/variants that may be unique to AA. In this study, we performed the first admixture mapping of DSM-IV alcohol dependence diagnosis, DSM-IV alcohol dependence criterion count, and two scores from the self-rating of effects of ethanol (SRE) as measures of response to alcohol: the first five times of using alcohol (SRE-5) and average of SRE across three times (SRE-T). Findings revealed a region on chromosome 4 that was genome-wide significant for SRE-5 (p value = 4.18E-05). Fine mapping did not identify a single causal variant to be associated with SRE-5; instead, conditional analysis concluded that multiple variants collectively explained
The direct estimation of heritability from genome-wide common variant data as implemented in the ... more The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for ...
Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study
Journal of the American Academy of Child and Adolescent Psychiatry, 2014
Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental d... more Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large…
Opioid receptors and their endogenous peptide ligands play important roles in the reward and rein... more Opioid receptors and their endogenous peptide ligands play important roles in the reward and reinforcement of drugs such as heroin, cocaine, and alcohol. The binding of dynorphins to the j-opioid receptor has been shown to produce aversive states, which may prevent the development of reinforcement. We genotyped SNPs throughout OPRK1, encoding the j-opioid receptor, and PDYN, which encodes its ligand prodynorphin, in a group of 1860 European American individuals from 219 multiplex alcohol dependent families. Family-based analyses demonstrated associations between alcohol dependence and multiple SNPs in the promoter and 3 0 end of PDYN, and in intron 2 of OPRK1. Haplotype analyses further supported the association of PDYN. Thus, variations in the genes encoding both the j-opioid receptor and its ligand, OPRK1 and PDYN, are associated with the risk for alcohol dependence; this makes biological sense as variations in either should affect signaling through the j-opioid system.
Group IIa phospholipase A 2 (GIIa PLA 2) is released by some cells in response to interleukin-1.... more Group IIa phospholipase A 2 (GIIa PLA 2) is released by some cells in response to interleukin-1. The purpose of this study was to determine whether interleukin-1 would stimulate the synthesis and release of GIIa PLA 2 from cardiomyocytes, and to define the role of p38 MAPK and cytosolic PLA 2 in the regulation of this process. Whereas GIIa PLA 2 mRNA was not identified in untreated cells, exposure to interleukin-1 resulted in the sustained expression of GIIa PLA 2 mRNA. Interleukin-1 also stimulated a progressive increase in cellular and extracellular GIIa PLA 2 protein levels and increased extracellular PLA 2 activity 70-fold. In addition, interleukin-1 stimulated the p38 MAPK-dependent activation of the downstream MAPK-activated protein kinase, MAPKAP-K2. Treatment with the p38 MAPK inhibitor, SB202190, decreased interleukin-1 stimulated MAPKAP-K2 activity, GIIa PLA 2 mRNA expression, GIIa PLA 2 protein synthesis, and the release of extracellular PLA 2 activity. Infection with an adenovirus encoding a constitutively active form of MKK6, MKK6(Glu), which selectively phosphorylates p38 MAPK, induced cellular GIIa PLA 2 protein synthesis and the release of GIIa PLA 2 and increased extracellular PLA 2 activity 3-fold. In contrast, infection with an adenovirus encoding a phosphorylation-resistant MKK6, MKK6(A), did not result in GIIa PLA 2 protein synthesis or release by unstimulated cardiomyocytes. In addition, infection with an adenovirus encoding MKK6(A) abrogated GIIa PLA 2 protein synthesis and release by interleukin-1-stimulated cells. These results provide direct evidence that p38 MAPK activation was necessary for interleukin-1induced synthesis and release of GIIa PLA 2 by cardiomyocytes.
Tourette syndrome (TS) is a neuropsychiatric disorder characterized by recurrent motor and vocal ... more Tourette syndrome (TS) is a neuropsychiatric disorder characterized by recurrent motor and vocal tics, often accompanied by obsessive-compulsive disorder and/ or attention-deficit/hyperactivity disorder. While the evidence for a genetic contribution is strong, its exact nature has yet to be clarified fully. There is now mounting evidence that the genetic risks for TS include both common and rare variants and may involve complex multigenic inheritance or, in rare cases, a single major gene. Based on recent progress in many other common disorders with apparently similar genetic architectures, it is clear that large patient cohorts and open-access repositories will be essential to further advance the field. To that end, the large multicenter Tourette International Collaborative Genetics (TIC Genetics) study was established. The goal of the TIC Genetics study is to undertake a comprehensive gene discovery effort, focusing both on familial genetic variants with large effects within multiply affected pedigrees and on de novo mutations ascertained through the analysis of apparently simplex parent-child trios with non-familial tics. The clinical data and biomaterials (DNA, transformed cell lines, RNA) are part of a sharing repository located within the National Institute for Mental Health Center for Collaborative Genomics Research on Mental Disorders, USA, and will be made available to the broad scientific community. This resource will ultimately facilitate better understanding of the pathophysiology of TS and related disorders and the development of novel therapies. Here, we describe the objectives and methods of the TIC Genetics study as a reference for future studies from our group and to facilitate collaboration between genetics consortia in the field of TS. Keywords Genes Á Methods Á Multiplex families Á Rare variants Á Repository Á Tourette syndrome Á Trios Members of the TIC Genetics Collaborative Group are listed under ''Appendix''.
Alcoholism: Clinical and Experimental Research, 2010
Background: Endophenotypes reflect more proximal effects of genes than diagnostic categories, hen... more Background: Endophenotypes reflect more proximal effects of genes than diagnostic categories, hence providing a more powerful strategy in searching for genes involved in complex psychiatric disorders. There is strong evidence suggesting the P3 amplitude of the event-related potential (ERP) as an endophenotype for the risk of alcoholism and other disinhibitory disorders. Recent studies demonstrated a crucial role of corticotropin releasing hormone receptor 1 (CRHR1) in the environmental stress response and ethanol self-administration in animal models. The aim of the present study was to test the potential associations between single-nucleotide polymorphisms (SNPs) in the CRHR1 gene and the quantitative trait, P3 amplitude during the processing of visual target signals in an oddball paradigm, as well as alcohol dependence diagnosis. Methods: We analyzed a sample from the Collaborative Study on the Genetics of Alcoholism (COGA) comprising 1049 Caucasian subjects from 209 families (including 472 alcohol-dependent individuals). Quantitative transmission disequilibrium test (QTDT) and family-based association test (FBAT) were used to test the association, and false discovery rate (FDR) was applied to correct for multiple comparisons. Results: Significant associations (p < 0.05) were found between the P3 amplitude and alcohol dependence with multiple SNPs in the CRHR1 gene. Conclusions: Our results suggest that CRHR1 may be involved in modulating the P3 component of the ERP during information processing and in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders.
Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported ... more Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared to family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE)
Alcoholism: Clinical and Experimental Research, 2013
Background-Despite the high heritability of alcohol dependence (AD), the genes found to be associ... more Background-Despite the high heritability of alcohol dependence (AD), the genes found to be associated with it account for only a small proportion of its total variability. The goal of this study was to identify and analyze phenotypes based on homogeneous classes of individuals to increase the power to detect genetic risk factors contributing to the risk of AD. Methods-The 7 individual DSM-IV criteria for AD were analyzed using latent class analysis (LCA) to identify classes defined by the pattern of endorsement of the criteria. A genome-wide association study was performed in 118 extended European American families (n = 2,322 individuals) densely affected with AD to identify genes associated with AD, with each of the seven DSM-IV criteria, and with the probability of belonging to two of three latent classes. Results-Heritability for DSM-IV AD was 61%, and ranged from 17-60% for the other phenotypes. A SNP in the olfactory receptor OR51L1 was significantly associated (7.3 × 10 −8) with the DSM-IV criterion of persistent desire to, or inability to, cut down on drinking. LCA revealed a three-class model: the "low risk" class (50%) rarely endorsed any criteria, and none met criteria for AD; the "moderate risk" class (33) endorsed primarily 4 DSM-IV criteria, and 48% met criteria for AD; the "high risk" class (17%) manifested high endorsement probabilities for most criteria and nearly all (99%) met criteria for AD One single nucleotide polymorphism (SNP) in a sodium leak channel NALCN demonstrated genome-wide significance with the high risk class (p=4.1 × 10 −8). Analyses in an independent sample did not replicate these associations. Conclusion-We explored the genetic contribution to several phenotypes derived from the DSM-IV alcohol dependence criteria. The strongest evidence of association was with SNPs in NALCN and OR51L1.
A broad region on chromosome 4q has been linked to alcohol dependence (alcoholism). We hypothesiz... more A broad region on chromosome 4q has been linked to alcohol dependence (alcoholism). We hypothesized that such broad linkage regions represent the combined action of multiple genes. Seeking to identify genes within that region that are associated with alcoholism, we have tested the association of NFKB1, located at 4q24, with alcoholism. NFKB1 encodes a 105 kDa transcription inhibitor that is cleaved to the 50 kDa DNA-binding subunit of the ubiquitous transcription factor NF-kB. NF-kB regulates many genes relevant to brain function, and its actions can be potentiated by ethanol; thus, NFKB1 is an excellent candidate gene for alcoholism. Nineteen SNPs in and near NFKB1 were analyzed in a sample of 219 multiplex alcoholic families of European American descent. Family-based association analyses detected significant evidence of association with eight SNPs and marginal evidence for five more. The association was driven by the affected individuals with earlier onset of alcoholism (55% of the sample with onset 21 years). Further analysis of the age of onset as a quantitative variable provided evidence for the association of 12 SNPs in this gene. Thus, variations in NFKB1 appear to affect the risk for alcoholism, particularly contributing to an earlier onset of the disease.
Genetics of Gilles De La Tourette Syndrome: Accelerating Discoveries Through Large-Scale Collaborative Efforts
European Neuropsychopharmacology
Overall Abstract Gilles de la Tourette Syndrome (TS) is a common, albeit still under-diagnosed, n... more Overall Abstract Gilles de la Tourette Syndrome (TS) is a common, albeit still under-diagnosed, neuropsychiatric disorder that is caused by a complex genetic basis, interacting with environmental factors. This symposium will showcase exciting findings from all current large-scale collaborative efforts aiming to elucidate the genetic background of TS, through diverse approaches and studies of several thousands of individuals with TS; genome-wide association studies (GWAS) aiming to identify common variants associated to the disorder, whole-exome sequencing approaches seeking rare variants, gene-expression studies aiming to identify the relative contribution of genetics versus environmental factors, and sophisticated approaches aiming to dissect complex and comorbid phenotypes. We will present novel TS susceptibility genes implicated on a genome-wide significance level either by GWAS, large-scale CNV scans or whole-exome sequencing and introduce heritable TS sub-phenotypes. We will also present large-scale GWAS meta-analysis of TS together with other, often comorbid neurodevelopmental disorders, such as obsessive-compulsive disorder, attention deficit hyperactivity disorder and autism. Finally, after more than two decades of active research aiming to identify the genetic background of TS etiology, we are on the verge of a new era, yielding exciting and rapid discoveries in the field of TS genetics. Investigators from around the world, representing multiple disciplines and scientific approaches, are joining their efforts in large-scale initiatives supported both by the European Union and US National funding agencies. Propelled by the gradual availability of large scale TS cohorts, novel methodologies for the study of both common and rare genetic variants, and importantly, sheer enthusiasm by multiple researchers working together across different countries, the new era of TS genetics holds the promise to identify novel targets for improved therapies.
The achievements of cell-based therapeutics have galvanized efforts to bring cell therapies to th... more The achievements of cell-based therapeutics have galvanized efforts to bring cell therapies to the market. To address the demands of the clinical and eventual commercial-scale production of cells, and with the increasing generation of large clinical datasets from chimeric antigen receptor T-cell immunotherapy, from transplants of engineered haematopoietic stem cells and from other promising cell therapies, an emphasis on biomanufacturing requirements becomes necessary. Robust infrastructure should address current limitations in cell harvesting, expansion, manipulation, purification, preservation and formulation, ultimately leading to successful therapy administration to patients at an acceptable cost. In this Review, we highlight case examples of cutting-edge bioprocessing technologies that improve biomanufacturing efficiency for cell therapies approaching clinical use. Cell therapeutics-which entails the use of human cells as medicines-promise to transform the treatment of a wide range of diseases, such as cancer, neurodegenerative disorders and autoimmune disorders, by enabling sophisticated mechanisms of action that small chemical compounds cannot provide. For example, the differentiation of stem cells into specialized cells, such as hormone-secreting endocrine cells, cytotoxic lymphocytes or tissue-regenerating cells, can be exploited for therapeutic properties. Also, cells can be genetically engineered to perform a wide range of functions 1-4 and, because of cell-homing properties 5 , can deliver drug payloads. Academic and industrial research and development efforts are typically focused on understanding how cell therapies can treat a diverse set of indications, as highlighted by the recent rise of phase I-III trials 6 (Fig. 1a). In fact, to date, commercial wins have been achieved at a relatively lower standard than expected from the pharmacological industry. On the basis of a semiquantitative analysis, the cell-therapy conversion rate from a phase III study to regulatory approval is estimated to be at 14.3%, which is considerably lower than the conversion rate (48.7%) of mature pharmaceutical drug classes showing new-drugapplication success with the United States Food and Drug Administration (FDA; Supplementary Table 1). Future market analyses are encouraged by groups such as the Alliance for Regenerative Medicine, to further quantify and track trends as more studies and regulatory approvals proceed. Recent approvals in the United States and the European Union for GSK, Tigenix, Novartis and Kite (a Gilead company) are bringing new enthusiasm for better-defined success criteria that help move more cell therapies to the marketplace. The promise of cell therapeutics comes with new challenges in reproducibly manufacturing and in administering cells to thousands of patients 7. It is important to recognize that methods that are sufficient for generating products on the scale of early pivotal clinical studies may not directly translate to commercial-scale yields and efficiencies. Therefore, beyond the success rate of current clinical trials, commercial-scale demands for cell therapeutics in common diseases will hamstring the supply of a cell therapy product (CTP) if not assessed at an early developmental stage (Fig. 1b). This gap in supply and demand will ultimately affect patients who may not be served by a CTP, simply due to unfilled prescriptions. The associated logistical and economic factors involved are not trivial: physical space, production time, human resources, consumables, waste generation (environmental impact) Aijaz et al.
High frequency in vivo loss of heterozygosity is primarily a consequence of mitotic recombination
We have used the adenine phosphoribosyltransferase gene (APRT; 16q24) to investigate the mechanis... more We have used the adenine phosphoribosyltransferase gene (APRT; 16q24) to investigate the mechanisms of loss of heterozygosity (LOH) in normal human somatic cells in vivo. APRT-deficient (APRT-/-, APRT-/0) T lymphocytes from the peripheral blood of four obligate APRT heterozygotes (APRT+/-) with characterized germ-line mutations were selected in medium containing 100 microM 2,6-diaminopurine. A total of 80 2,6-diaminopurine-resistant T-cell clones from 2 of the heterozygotes were analyzed for this study. The presence or absence of LOH of proximal linked microsatellite repeat markers was used to divide the clones into two groups: (a) those in which LOH was likely due to localized changes in APRT (e.g., point mutations); and (b) those with LOH at additional loci. A total of 61 clones (76%) exhibited LOH of linked microsatellite repeat markers at different locations on 16q, which extended from the smallest measured region (<5.5 cM) to the entire 16q arm. The remaining 19 clones (24%)...
International journal of psychophysiology : official journal of the International Organization of Psychophysiology, May 28, 2016
Differences in fast beta (20-28 Hz) electroencephalogram (EEG) oscillatory activity distinguish s... more Differences in fast beta (20-28 Hz) electroencephalogram (EEG) oscillatory activity distinguish some individuals with psychiatric and substance use disorders, suggesting that it may be a useful endophenotype for studying the genetics of disorders characterized by neural hyper-excitability. Despite the high heritability estimates provided by twin and family studies, there have been relatively few genetic studies of beta EEG, and to date only one genetic association finding has replicated (i.e., GABRA2). In a sample of 1,564 individuals from 117 families of European Ancestry (EA) drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Genome-Wide Association Study (GWAS) on resting-state fronto-central fast beta EEG power, adjusting regression models for family relatedness, age, sex, and ancestry. To further characterize genetic findings, we examined the functional and behavioral significance of GWAS findings. Three intronic variants located within DSE ...
DNA double‐strand break repair in mouse embryonic stem cells
The FASEB Journal
Genome‐wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐ and European‐Americans
Genes, Brain and Behavior
Genome‐wide association studies of alcohol dependence, DSM‐IV criterion count, and individual criteria
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Papers by Jay Tischfield