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Nishi-Tokyo-shi, Japan

Chan G.,University of Connecticut | Gelernter J.,Yale University | Gelernter J.,Healthcare Center | Oslin D.,University of Pennsylvania | And 2 more authors.
Addiction | Year: 2011

Aims To identify and validate homogeneous subtypes of opioid use and related behaviors. Design Family-based and case-control genetic studies of opioid and/or cocaine dependence. Settings Clinical and general community samples from Connecticut, Massachusetts, Pennsylvania and South Carolina. Participants A total of 4061 individuals (2003 individuals from 835 families and 2058 unrelated individuals) recruited to participate in genetic studies. Measurements The computer-assisted Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) was used to assess participants' demographics, medical history, substance use behaviors and disorders and other psychiatric disorders. Findings Five homogeneous subtypes were identified, which differed on opioid-related measures, demographics and prevalence rates of substance use and psychiatric disorders. Heritability estimates for the two most severely affected subtypes exceeded 0.60. Conclusions An empirical approach based on opioid use and related behaviors can yield homogeneous subtypes that could be of value in gene finding for opioid dependence. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction. Source

Bi J.,University of Connecticut | Gelernter J.,Yale University | Gelernter J.,Healthcare Center | Sun J.,University of Connecticut | And 2 more authors.
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2014

Because DSM-IV cocaine dependence (CD) is heterogeneous, it is not an optimal phenotype to identify genetic variation contributing to risk for cocaine use and related behaviors (CRBs). We used a cluster analytic method to differentiate homogeneous, highly heritable subtypes of CRBs and to compare their utility with that of the DSM-IV CD as traits for genetic association analysis. Clinical features of CRBs and co-occurring disorders were obtained via a poly-diagnostic interview administered to 9,965 participants in genetic studies of substance dependence. A subsample of subjects (N=3,443) were genotyped for 1,350 single nucleotide polymorphisms (SNPs) selected from 130 candidate genes related to addiction. Cluster analysis of clinical features of the sample yielded five subgroups, two of which were characterized by heavy cocaine use and high heritability: a heavy cocaine use, infrequent intravenous injection group and an early-onset, heavy cocaine use, high comorbidity group. The utility of these traits was compared with the CD diagnosis through association testing of 2,320 affected subjects and 480 cocaine-exposed controls. Analyses examined both single SNP (main) and SNP-SNP interaction (epistatic) effects, separately for African-Americans and European-Americans. The two derived subtypes showed more significant P values for 6 of 8 main effects and 7 of 8 epistatic effects. Variants in the CLOCK gene were significantly associated with the heavy cocaine use, infrequent intravenous injection group, but not with the DSM-IV diagnosis of CD. These results support the utility of subtypes based on CRBs to detect risk variants for cocaine addiction. © 2013 Wiley Periodicals, Inc. Source

Chen X.,Yale University | Listman J.B.,Yale University | Slack F.J.,Yale University | Gelernter J.,Yale University | And 3 more authors.
Genetic Epidemiology | Year: 2012

Next-generation sequencing is widely used to study complex diseases because of its ability to identify both common and rare variants without prior single nucleotide polymorphism (SNP) information. Pooled sequencing of implicated target regions can lower costs and allow more samples to be analyzed, thus improving statistical power for disease-associated variant detection. Several methods for disease association tests of pooled data and for optimal pooling designs have been developed under certain assumptions of the pooling process, for example, equal/unequal contributions to the pool, sequencing depth variation, and error rate. However, these simplified assumptions may not portray the many factors affecting pooled sequencing data quality, such as PCR amplification during target capture and sequencing, reference allele preferential bias, and others. As a result, the properties of the observed data may differ substantially from those expected under the simplified assumptions. Here, we use real datasets from targeted sequencing of pooled samples, together with microarray SNP genotypes of the same subjects, to identify and quantify factors (biases and errors) affecting the observed sequencing data. Through simulations, we find that these factors have a significant impact on the accuracy of allele frequency estimation and the power of association tests. Furthermore, we develop a workflow protocol to incorporate these factors in data analysis to reduce the potential biases and errors in pooled sequencing data and to gain better estimation of allele frequencies. The workflow, Psafe, is available at http://bioinformatics.med.yale.edu/group/. © 2012 Wiley Periodicals, Inc. Source

Gelernter J.,Yale University | Gelernter J.,Healthcare Center | Sherva R.,Boston University | Koesterer R.,Boston University | And 5 more authors.
Molecular Psychiatry | Year: 2014

We report a genome-wide association study (GWAS) for cocaine dependence (CD) in three sets of African- and European-American subjects (AAs and EAs, respectively) to identify pathways, genes and alleles important in CD risk. The discovery GWAS data set (n=5697 subjects) was genotyped using the Illumina OmniQuad microarray (8 90 000 analyzed single-nucleotide polymorphisms (SNPs)). Additional genotypes were imputed based on the 1000 Genomes reference panel. Top-ranked findings were evaluated by incorporating information from publicly available GWAS data from 4063 subjects. Then, the most significant GWAS SNPs were genotyped in 2549 independent subjects. We observed one genome-wide-significant (GWS) result: rs2629540 at the FAM53B ('family with sequence similarity 53, member B') locus. This was supported in both AAs and EAs; P-value (meta-analysis of all samples)=4.28 × 10 -8. The gene maps to the same chromosomal region as the maximum peak we observed in a previous linkage study. NCOR2 (nuclear receptor corepressor 2) SNP rs150954431 was associated with P=1.19 × 10 -9 in the EA discovery sample. SNP rs2456778, which maps to CDK1 ('cyclin-dependent kinase 1'), was associated with cocaine-induced paranoia in AAs in the discovery sample only (P=4.68 × 10 -8). This is the first study to identify risk variants for CD using GWAS. Our results implicate novel risk loci and provide insights into potential therapeutic and prevention strategies. © 2014 Macmillan Publishers Limited. Source

Kim Y.-J.,Healthcare Center | Lee W.P.,Dr. Lees Clinic of Internal Medicine
Journal of the Korean Medical Association | Year: 2014

Whether or not insurance covers new health technology has a great effect on the extent of its acceptance and diffusion. Thus many stakeholders vie to participate in determining insurance reimbursement regulations. This paper explains the process by which new health care technology is added to the coverage list in the Republic of Korea,with each checkpoint explained. Our paper also argues that the implication of the listing process of Korean insurance coverage should be modified in the area such as what is the principle of insurance coverage and who will decide the acceptance criteria of health technology, safety, effectiveness, economic feasibility, and relative value. Source

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