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Selected AbstractsSubtypes of major depression in substance dependenceADDICTION, Issue 10 2009Mark J. Niciu ABSTRACT Aims This study evaluated features that differentiate subtypes of major depressive episode (MDE) in the context of substance dependence (SD). Design Secondary data analysis using pooled data from family-based and case,control genetic studies of SD. Setting Community recruitment through academic medical centers. Participants A total of 1929 unrelated subjects with alcohol and/or drug dependence. Measurements Demographics, diagnostic criteria for psychiatric and substance use disorders and related clinical features were obtained using the Semi-Structured Assessment for Drug Dependence and Alcoholism. We compared four groups: no life-time MDE (no MDE), independent MDE only (I-MDE), substance-induced MDE only (SI-MDE) and both types of MDE. Findings Psychiatric measures were better predictors of MDE subtype than substance-related or socio-demographic ones. Subjects with both types of MDE reported more life-time depressive symptoms and comorbid anxiety disorders and were more likely to have attempted suicide than subjects with I-MDE or SI-MDE. Subjects with both types of MDE, like those with I-MDE, were also more likely than subjects with SI-MDE to be alcohol-dependent only than either drug-dependent only or both alcohol- and drug-dependent. Conclusions SD individuals with both types of MDE have greater psychiatric severity than those with I-MDE only or SI-MDE only. These and other features that distinguish among the MDE subtypes have important diagnostic and potential therapeutic implications. [source] Protein deficiency balance as a predictor of clinical outcome in hereditary spherocytosisEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2005S. Rocha Abstract:, Vertical and horizontal interactions between membrane constituents account for integrity, strength and deformability of the erythrocyte. Disruption of vertical interactions caused by membrane protein deficiencies in hereditary spherocytosis (HS), favor membrane vesiculation with development of spherocytic cells. Our aim was to evaluate the hematological and clinical presentation of HS according to the type and amount of protein deficiency. We studied 81 Portuguese individuals, 71 belonging to 21 families plus 10 unrelated subjects, and found that 51 of them were HS patients. Patients were classified as presenting mild, typical or severe HS, according to laboratory results and clinical follow-up. We performed screening tests and the standardized electrophoretic membrane protein analysis to identify and quantify protein deficiencies. We found band 3 and ankyrin deficiencies as the major causes for HS. The ratios between the value of the primary and/or secondary protein deficiencies showed significantly different values according to the severity of HS, and a significant inverse correlation with the severity of HS was observed. In mild HS, the ratios between protein deficiencies reflected equivalent protein deficiencies, while an unbalance was observed in typical HS, which was enhanced in severe HS. Our data suggest that the relative quantification of each major membrane protein and of the ratios between the values of protein deficiencies may be helpful in providing additional data about the clinical outcome of HS. [source] Distribution and frequency of , -thalassemia mutations in northwestern and central GreeceEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2003I. Georgiou Abstract: Objectives : , -Thalassemia is a common autosomal recessive disorder resulting from over 200 different mutations of the , -globin genes. The spectrum of , -thalassemia mutations in Greece has been previously described in the population of the capital city of Athens, or in , -thalassemia patients having transfusion therapy. The aim of the present study was to identify the distribution of the most common , -thalassemia mutations in the population of northwestern and central Greece. Methods : The data for this study were derived from a total of 1130 unrelated subjects including 46 , -thalassemia major, three , -thalassemia intermedia and 1081 carriers identified in our antenatal screening program. , -Thalassemia mutations were identified by ARMS, DGGE and Reverse Dot Blot. Results : The most common mutation, IVS-I-110, is followed, in order of frequency, by the mutations Cd-39, IVS-I-1, IVS-II-1, Cd-6, IVS-I-6, IVS-I-5, IVS-II-745, Cd-5 and 44 bp del. IVS-I-110 and Cd-39 frequencies are similar with those found in other Balkan countries. Significant differences in regional distribution were observed. The results showed a clear drift of the distribution of the most frequent IVS-I-110 mutation in the south,north (29.4, 40.0, 44.6 and 61.7%) and the east,west axis (31.8 and 44.6%). Conclusions : Population screening and prenatal diagnosis are significantly facilitated by these data. Furthermore, the detailed distribution tables of , -thalassemia mutations are essential for counseling and extraction of genetic diversity estimates for population genetic studies in other inherited disorders. [source] Pleiotropy and principal components of heritability combine to increase power for association analysisGENETIC EPIDEMIOLOGY, Issue 1 2008Lambertus Klei Abstract When many correlated traits are measured the potential exists to discover the coordinated control of these traits via genotyped polymorphisms. A common statistical approach to this problem involves assessing the relationship between each phenotype and each single nucleotide polymorphism (SNP) individually (PHN); and taking a Bonferroni correction for the effective number of independent tests conducted. Alternatively, one can apply a dimension reduction technique, such as estimation of principal components, and test for an association with the principal components of the phenotypes (PCP) rather than the individual phenotypes. Building on the work of Lange and colleagues we develop an alternative method based on the principal component of heritability (PCH). For each SNP the PCH approach reduces the phenotypes to a single trait that has a higher heritability than any other linear combination of the phenotypes. As a result, the association between a SNP and derived trait is often easier to detect than an association with any of the individual phenotypes or the PCP. When applied to unrelated subjects, PCH has a drawback. For each SNP it is necessary to estimate the vector of loadings that maximize the heritability over all phenotypes. We develop a method of iterated sample splitting that uses one portion of the data for training and the remainder for testing. This cross-validation approach maintains the type I error control and yet utilizes the data efficiently, resulting in a powerful test for association. Genet. Epidemiol. 2007. © 2007 Wiley-Liss, Inc. [source] Resampling-based multiple hypothesis testing procedures for genetic case-control association studies,GENETIC EPIDEMIOLOGY, Issue 6 2006Bingshu E. Chen Abstract In case-control studies of unrelated subjects, gene-based hypothesis tests consider whether any tested feature in a candidate gene,single nucleotide polymorphisms (SNPs), haplotypes, or both,are associated with disease. Standard statistical tests are available that control the false-positive rate at the nominal level over all polymorphisms considered. However, more powerful tests can be constructed that use permutation resampling to account for correlations between polymorphisms and test statistics. A key question is whether the gain in power is large enough to justify the computational burden. We compared the computationally simple Simes Global Test to the min,P test, which considers the permutation distribution of the minimum p -value from marginal tests of each SNP. In simulation studies incorporating empirical haplotype structures in 15 genes, the min,P test controlled the type I error, and was modestly more powerful than the Simes test, by 2.1 percentage points on average. When disease susceptibility was conferred by a haplotype, the min,P test sometimes, but not always, under-performed haplotype analysis. A resampling-based omnibus test combining the min,P and haplotype frequency test controlled the type I error, and closely tracked the more powerful of the two component tests. This test achieved consistent gains in power (5.7 percentage points on average), compared to a simple Bonferroni test of Simes and haplotype analysis. Using data from the Shanghai Biliary Tract Cancer Study, the advantages of the newly proposed omnibus test were apparent in a population-based study of bile duct cancer and polymorphisms in the prostaglandin-endoperoxide synthase 2 (PTGS2) gene. Genet. Epidemiol. 2006. Published 2006 Wiley-Liss, Inc. [source] Stratified case sampling and the use of family controlsGENETIC EPIDEMIOLOGY, Issue 3 2001Kimberly D. Siegmund Abstract We compare the asymptotic relative efficiency (ARE) of different study designs for estimating gene and gene-environment interaction effects using matched case-control data. In the sampling schemes considered, cases are selected differentially based on their family history of disease. Controls are selected either from unrelated subjects or from among the case's unaffected siblings and cousins. Parameters are estimated using weighted conditional logistic regression, where the likelihood contributions for each subject are weighted by the fraction of cases sampled sharing the same family history. Results showed that compared to random sampling, over-sampling cases with a positive family history increased the efficiency for estimating the main effect of a gene for sib-control designs (103,254% ARE) and decreased efficiency for cousin-control and population-control designs (68,94% ARE and 67,84% ARE, respectively). Population controls and random sampling of cases were most efficient for a recessive gene or a dominant gene with an relative risk less than 9. For estimating gene-environment interactions, over-sampling positive-family-history cases again led to increased efficiency using sib controls (111,180% ARE) and decreased efficiency using population controls (68,87% ARE). Using case-cousin pairs, the results differed based on the genetic model and the size of the interaction effect; biased sampling was only slightly more efficient than random sampling for large interaction effects under a dominant gene model (relative risk ratio = 8, 106% ARE). Overall, the most efficient study design for studying gene-environment interaction was the case-sib-control design with over-sampling of positive-family-history-cases. Genet. Epidemiol. 20:316,327, 2001. © 2001 Wiley-Liss, Inc. [source] Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency,HUMAN MUTATION, Issue 8 2010Fang-Yuan Li Abstract Systemic primary carnitine deficiency (CDSP) is caused by recessive mutations in the SLC22A5 (OCTN2) gene encoding the plasmalemmal carnitine transporter and characterized by hypoketotic hypoglycemia, and skeletal and cardiac myopathy. The entire coding regions of the OCTN2 gene were sequenced in 143 unrelated subjects suspected of having CDSP. In 70 unrelated infants evaluated because of abnormal newborn screening (NBS) results, 48 were found to have at least 1 mutation/unclassified missense variant. Twenty-eight of 33 mothers whose infants had abnormal NBS results were found to carry at least 1 mutation/unclassified missense variant, including 11 asymptomatic mothers who had 2 mutations. Therefore, sequencing of the OCTN2 gene is recommended for infants with abnormal NBS results and for their mothers. Conversely, 52 unrelated subjects were tested due to clinical indications other than abnormal NBS and only 14 of them were found to have at least one mutation/unclassified variant. Custom designed oligonucleotide array CGH analysis revealed a heterozygous ,1.6 Mb deletion encompassing the entire OCTN2 gene in one subject who was apparently homozygous for the c.680G>A (p.R227H) mutation. Thus, copy number abnormalities at the OCTN2 locus should be considered if by sequencing, an apparently homozygous mutation or only one mutant allele is identified. ©2010 Wiley-Liss, Inc. [source] A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy,HUMAN MUTATION, Issue 6 2008Montserrat Rodríguez-Ballesteros Abstract Autosomal recessive nonsyndromic hearing impairment (NSHI) is a heterogeneous condition, for which 53 genetic loci have been reported, and 29 genes have been identified to date. One of these, OTOF, encodes otoferlin, a membrane-anchored calcium-binding protein that plays a role in the exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse. We have investigated the prevalence and spectrum of deafness-causing mutations in the OTOF gene. Cohorts of 708 Spanish, 83 Colombian, and 30 Argentinean unrelated subjects with autosomal recessive NSHI were screened for the common p.Gln829X mutation. In compound heterozygotes, the second mutant allele was identified by DNA sequencing. In total, 23 Spanish, two Colombian and two Argentinean subjects were shown to carry two mutant alleles of OTOF. Of these, one Colombian and 13 Spanish subjects presented with auditory neuropathy. In addition, a cohort of 20 unrelated subjects with a diagnosis of auditory neuropathy, from several countries, was screened for mutations in OTOF by DNA sequencing. A total of 11 of these subjects were shown to carry two mutant alleles of OTOF. In total, 18 pathogenic and four neutral novel alleles of the OTOF gene were identified. Haplotype analysis for markers close to OTOF suggests a common founder for the novel c.2905_2923delinsCTCCGAGCGCA mutation, frequently found in Argentina. Our results confirm that mutation of the OTOF gene correlates with a phenotype of prelingual, profound NSHI, and indicate that OTOF mutations are a major cause of inherited auditory neuropathy. Hum Mutat 29(6), 823,831, 2008. © 2008 Wiley-Liss, Inc. [source] Hip geometry variation is associated with bone mineralization pathway gene variants: The framingham studyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2010Ching-Lung Cheung Abstract Mineralization of bone matrix is an important process in bone formation; thus defects in mineralization have been implicated in bone mineral density (BMD) and bone structure alterations. Three central regulators of phosphate balance, ALPL, ANKH, and ENPP1, are central in the matrix mineralization process; therefore, the genes encoding them are considered important candidates genes for BMD and bone geometry. To test for an association between these three candidate genes and BMD and bone geometry traits, 124 informative single-nucleotide polymorphisms (SNPs) were selected and genotyped in 1513 unrelated subjects from the Framingham offspring cohort. Initial results showed that SNP rs1974201 in the gene ENPP1 was a susceptibility variant associated with several hip geometric indices, with the strongest p value of 3.8,×,10,7 being observed for femoral neck width. A few modest associations were observed between SNPs in or near ALPL and several bone traits, but no association was observed with ANKH. The association signals observed for SNPs around rs1974201 were attenuated after conditional analysis on rs1974201. Transcription factor binding-site prediction revealed that the HOXA7 binding site was present in the reference sequence with the major allele, whereas this potential binding site is lost in the sequence with the minor allele of rs1974201. In conclusion, we found evidence for association of bone geometry variation with an SNP in ENPP1, a gene in the mineralization pathway. The alteration of a binding site of the deregulator of extracellular matrix HOXA7 warrants further investigation. © 2010 American Society for Bone and Mineral Research [source] Program Report: GENECOUNTING Support ProgramsANNALS OF HUMAN GENETICS, Issue 2 2006D. Curtis We describe a suite of programs which enhance the usability of GENECOUNTING, a program for estimating haplotype frequencies in unrelated subjects. The programs, called RUNGC, SCANASSOC, COMPGR, SCANGROUP and LDPAIRS, carry out likelihood ratio tests and permutation tests to detect differences in haplotype frequencies between cases and controls,or between predefined groups, and output likely haplotype assignments and tables of linkage disequilibrium statistics between all pairs of markers in a dataset. [source] | |||||||||||||