The copy number variation (CNV) is a type of genetic variation in the genome. It is measured based on signal intensity measures and can be assessed repeatedly to reduce the uncertainty in PCR-based typing. Studies have shown that CNVs may lead to phenotypic variation and modification of disease expression. Various challenges exist, however, in the exploration of CNV-disease association. Here we construct latent variables to infer the discrete CNV values and to estimate the probability of mutations. In addition, we propose to pool rare variants to increase the statistical power and we conduct family studies to mitigate the computational burden in determining the composition of CNVs on each chromosome. To explore in a stochastic sense the association between the collapsing CNV variants and disease status, we utilize a Bayesian hierarchical model incorporating the mutation parameters. This model assigns integers in a probabilistic sense to the quantitatively measured copy numbers, and is able to test simultaneously the association for all variants of interest in a regression framework. This integrative model can account for the uncertainty in copy number assignment and differentiate if the variation was de novo or inherited on the basis of posterior probabilities. For family studies, this model can accommodate the dependence within family members and among repeated CNV data. Moreover, the Mendelian rule can be assumed under this model and yet the genetic variation, including de novo and inherited variation, can still be included and quantified directly for each individual. Finally, simulation studies show that this model has high true positive and low false positive rates in the detection of de novo mutation.
Bayesian model; CNV association test; de novo CNV detection; schizophrenia multiplex family; random mutation parameter
Genes, environment, and the interaction between them are each known to play an important role in the risk for developing complex diseases such as metabolic syndrome. For environmental factors, most studies focused on the measurements observed at the individual level, and therefore can only consider the gene-environment interaction at the same individual scale. Indeed the group-level (called contextual) environmental variables, such as community factors and the degree of local area development, may modify the genetic effect as well. To examine such cross-level interaction between genes and contextual factors, a flexible statistical model quantifying the variability of the genetic effects across different categories of the contextual variable is in need. With a Bayesian generalized linear mixed-effects model with an unconditional likelihood, we investigate whether the individual genetic effect is modified by the group-level residential environment factor in a matched case-control metabolic syndrome study. Such cross-level interaction is evaluated by examining the heterogeneity in allelic effects under various contextual categories, based on posterior samples from Markov chain Monte Carlo methods. The Bayesian analysis indicates that the effect of rs1801282 on metabolic syndrome development is modified by the contextual environmental factor. That is, even among individuals with the same genetic component of PPARG_Pro12Ala, living in a residential area with low availability of exercise facilities may result in higher risk. The modification of the group-level environment factors on the individual genetic attributes can be essential, and this Bayesian model is able to provide a quantitative assessment for such cross-level interaction. The Bayesian inference based on the full likelihood is flexible with any phenotype, and easy to implement computationally. This model has a wide applicability and may help unravel the complexity in development of complex diseases.
Schizophrenia patients frequently display reduced niacin flush responses, and similar characteristics are also observed in their nonpsychotic relatives. This study aimed to identify loci influencing flush response to niacin in schizophrenia using genome-wide quantitative linkage scan. In a nationwide sample of families with at least 2 siblings affected with schizophrenia in each family, 115 families that had at least 2 affected siblings with information on the niacin skin test were subjected to quantitative trait loci linkage analysis, either involving affected individuals only or the whole family. Nonparametric linkage z (NPL-Z) scores were calculated for each of 386 microsatellite markers spaced at an average of 9-cM intervals. Niacin patches of 3 concentrations (0.001M, 0.01, and 0.1M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. Determination of genome-wide empirical significance was implemented using 1000 simulated genome scans. One linkage peak attaining genome-wide significance was identified at chromosomal region 14q32.12 for 0.01M concentration at 5 minutes (NPL-Z scores = 3.39, genome-wide empirical P = .03) in affected individuals, and the corresponding linkage signal remained strong (NPL-Z scores = 2.87) for the analyses of the whole family. This locus is distinct from the chromosomal region identified in the previous genome-wide scan for the diagnosis of schizophrenia, and the signal was higher than the peak linkage signal in that study. These findings indicate that there might be modifier or susceptibility-modifier genes at 14q32.12 for schizophrenia-related attenuation of flush response to niacin.
endophenotype; relative pair; identical by descent; nonparametric linkage z score; modifier gene; susceptibility-modifier gene
Introduction and Aims
Methamphetamine use leads to increased likelihood of premature death. The authors investigated the causes of death and risk of mortality in a large cohort of patients with methamphetamine dependence.
Design and Methods
A cohort of 1,254 subjects with methamphetamine dependence, admitted to a psychiatric center in Taiwan from January 1990 to December 2007, was retrospectively studied. Diagnostic and sociodemographic data for each subject were extracted from the medical records based on a chart review process. Mortality data were obtained by linking to the National Death Certification System and standardised mortality ratios (SMRs) were estimated. The risk and protective factors for all-cause deaths were explored by means of survival analyses.
During the study period, 130 patients died. Of them, 63.1% died unnatural deaths, while the remaining 36.9% died natural deaths. The 1-year cumulative rates for unnatural and natural deaths were 0.018 and 0.006, respectively and the 5-year rates were 0.046 and 0.023, respectively. The cohort had excessive mortality (SMR = 6.02), and women had a higher SMR for unnatural deaths than men (26.19 vs. 9.82, P = 0.001). For all-cause deaths, comorbiditywith other substance use disorders was associated with increased risk of death, despite that being married was associated with a reduced risk.
Discussion and Conclusions
A substantial proportion of the deceased died natural deaths, but most died unnatural deaths. The findings show significant evidence to provide valuable insight into premature deaths among methamphetamine-dependent users. This information is valuable for development of prevention and intervention programs.
methamphetamine; cohort; mortality; natural death; unnatural death
Existing studies have found the relationship between handedness and schizotypy to be inconsistent and had limited generalizability since only highly homogeneous groups have been investigated. This study aimed to examine the relation between handedness and the four schizotypal factors identified from a previous confirmatory factor analysis in a population of high familial loading for schizophrenia. Study subjects consisted of nonpsychotic first-degree relatives (850 parents and 334 siblings) of sib-pairs who were co-affected with schizophrenia. All participants were interviewed with the Diagnostic Interview for Genetic Studies, which contains a section of the modified Structured Interview for Schizotypy, and the Annett handedness questionnaire. Both categorical and continuous indicators for handedness were examined. Non-right handed siblings of schizophrenia patients displayed more positive schizotypal features than their right handed counterparts when the two-way Annett's handedness classification was adopted. No association was found when handedness was treated as continuous. The relationship between handedness and schizotypy was insignificant for parents probably due to the strong social pressure against left-handedness. We concluded that categorical non-right handedness was associated with positive schizotypy in nonpsychotic siblings of schizophrenia patients. The results indicate that an atypical cerebral lateralization underlying non-right handedness may be also a contributing factor to positive schizotypy.
positive schizotypy; handedness; familial loading; schizophrenia
Methamphetamine is one of the fastest growing illicit drugs worldwide, causing multiple organ damage and excessive natural deaths. The authors aimed to identify potential laboratory indices and clinical characteristics associated with natural death through a two-phase study.
Methamphetamine-dependent patients (n = 1,254) admitted to a psychiatric center in Taiwan between 1990 and 2007 were linked with a national mortality database for causes of death. Forty-eight subjects died of natural causes, and were defined as the case subjects. A time-efficient sex- and age-matched nested case-control study derived from the cohort was conducted first to explore the potential factors associated with natural death through a time-consuming standardized review of medical records. Then the identified potential factors were evaluated in the whole cohort to validate the findings.
In phase I, several potential factors associated with natural death were identified, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), comorbid alcohol use disorder, and the prescription of antipsychotic drugs. In phase II, these factors were confirmed in the whole cohort using survival analysis. For the characteristics at the latest hospital admission, Cox proportional hazards models showed that the adjusted hazard ratios for natural death were 6.75 (p<0.001) in the group with markedly elevated AST (>80 U/L) and 2.66 (p<0.05) in the group with mildly elevated AST (40–80 U/L), with reference to the control group (<40 U/L). As for ALT, the adjusted hazard ratios were 5.41 (p<0.001), and 1.44 (p>0.05). Comorbid alcohol use disorder was associated with an increased risk of natural death, whereas administration of antipsychotic drugs was not associated with lowered risk.
This study highlights the necessity of intensive follow-up for those with elevated AST and ALT levels and comorbid alcohol use disorder for preventing excessive natural deaths.
As schizophrenia is genetically and phenotypically heterogeneous, targeting genetically informative phenotypes may help identify greater linkage signals. The aim of the study is to evaluate the genetic linkage evidence for schizophrenia in subsets of families with earlier age at onset or greater neurocognitive deficits.
Patients with schizophrenia (n = 1,207) and their first-degree relatives (n = 1,035) from 557 families with schizophrenia were recruited from six data collection field research centers throughout Taiwan. Subjects completed a face-to-face semi-structured interview, the Continuous Performance Test (CPT), the Wisconsin Card Sorting Test, and were genotyped with 386 microsatellite markers across the genome.
A maximum nonparametric logarithm of odds (LOD) score of 4.17 at 2q22.1 was found in 295 families ranked by increasing age at onset, which had significant increases in the maximum LOD score compared with those obtained in initial linkage analyses using all available families. Based on this subset, a further subsetting by false alarm rate on the undegraded and degraded CPT obtained further increase in the nested subset-based LOD on 2q22.1, with a score of 7.36 in 228 families and 7.71 in 243 families, respectively.
We found possible evidence of linkage on chromosome 2q22.1 in families of schizophrenia patients with more CPT false alarm rates nested within the families with younger age at onset. These results highlight the importance of incorporating genetically informative phenotypes in unraveling the complex genetics of schizophrenia.
Haplotype association studies based on family genotype data can provide more biological information than single marker association studies. Difficulties arise, however, in the inference of haplotype phase determination and in haplotype transmission/non-transmission status. Incorporation of the uncertainty associated with haplotype inference into regression models requires special care. This task can get even more complicated when the genetic region contains a large number of haplotypes. To avoid the curse of dimensionality, we employ a clustering algorithm based on the evolutionary relationship among haplotypes and retain for regression analysis only the ancestral core haplotypes identified by it. To integrate the three sources of variation, phase ambiguity, transmission status and ancestral uncertainty, we propose an uncertainty-coding matrix which combines these three types of variability simultaneously. Next we evaluate haplotype risk with the use of such a matrix in a Bayesian conditional logistic regression model. Simulation studies and one application, a schizophrenia multiplex family study, are presented and the results are compared with those from other family based analysis tools such as FBAT. Our proposed method (Bayesian regression using uncertainty-coding matrix, BRUCM) is shown to perform better and the implementation in R is freely available.
Positive alcohol outcome expectancy has consistently been linked with problematic drinking, but there is little population-based evidence on its role on early stages of drinking in childhood. The present study seeks to understand the extent to which drinking of family members is differentially associated with the endorsement of alcohol expectancy in late childhood.
A representative sample of 4th and 6th graders (N = 2455) drawn from 28 public schools in an urban region of Taiwan completed a self-administered paper-and-pencil questionnaire. Each student provided information on alcohol expectancy, drinking experiences, and individual and family attributes. Complex survey analyses were performed to evaluate the relationship, with stratification by children's alcohol drinking history.
An estimated 29% of the 4th graders and 43% of the 6th graders had initiated alcohol consumption (over 40% of them had drank on three or more occasions). Alcohol drinking-related differences appear in both the endorsement and the correlates of alcohol expectancy. Positive alcohol expectancy was strongly associated with family drinking, particularly the dimension of "enhanced social behaviors"; negative alcohol expectancy was inversely associated with drinking frequency. Among alcohol naïve children, significant connections appear between paternal drinking and three dimensions of positive alcohol expectancy (i.e., enhanced social behaviors:βwt = 0.15, promoting relaxation or tension reduction:βwt = 0.18, and global positive transformation:βwt = 0.22).
Individual tailored strategies that address family influences on alcohol expectancy may be needed in prevention programs targeting drinking behaviors in children.
This study aimed to examine: 1) the relationship between being a runaway and the time since the first absconding event and adolescent substance use; 2) whether different kinds of psychoactive substances have a different temporal relationship to the first absconding event; and 3) whether the various reasons for the first absconding event are associated with different risks of substance use.
Participants were drawn from the 2004-2006 nationwide outreach programs across 26 cities/towns in Taiwan. A total of 17,133 participants, age 12-18 years, who completed an anonymous questionnaire on their experience of running away and substances use and who were now living with their families, were included in the analysis.
The lifetime risk of tobacco, alcohol, betel nut, and illegal drug/inhalant use increased steadily from adolescents who had experienced a trial runaway episode (one time lasting ≤ 1 day), to those with extended runaway experience (≥ 2 times or lasting > 1 day), when compared to those who had never ran away. Adolescents who had their first running away experience > 6 months previously had a greater risk of betel nut or illegal drug/inhalant use over the past 6-months than those with a similar experience within the last 6 months. Both alcohol and tobacco use were most frequently initiated before the first running away, whereas both betel nut and illegal drug/inhalant use were most frequently initiated after this event. When adolescents who were fleeing an unsatisfactory home life were compared to those who ran away for excitement, the risk of alcohol use was similar but the former tended to have a higher risk of tobacco, betel nut, and illegal drug/inhalant use.
More significant running away and a longer time since the first absconding experience were associated with more advanced substance involvement among adolescents now living in a family setting. Once adolescents had left home, they developed additional psychoactive substance problems, regardless of their reasons for running away. These findings have implications for caregivers, teachers, and healthcare workers when trying to prevent and/or intervening in adolescent substance use.
Selection of influential genes with microarray data often faces the difficulties of a large number of genes and a relatively small group of subjects. In addition to the curse of dimensionality, many gene selection methods weight the contribution from each individual subject equally. This equal-contribution assumption cannot account for the possible dependence among subjects who associate similarly to the disease, and may restrict the selection of influential genes.
A novel approach to gene selection is proposed based on kernel similarities and kernel weights. We do not assume uniformity for subject contribution. Weights are calculated via regularized least squares support vector regression (RLS-SVR) of class levels on kernel similarities and are used to weight subject contribution. The cumulative sum of weighted expression levels are next ranked to select responsible genes. These procedures also work for multiclass classification. We demonstrate this algorithm on acute leukemia, colon cancer, small, round blue cell tumors of childhood, breast cancer, and lung cancer studies, using kernel Fisher discriminant analysis and support vector machines as classifiers. Other procedures are compared as well.
This approach is easy to implement and fast in computation for both binary and multiclass problems. The gene set provided by the RLS-SVR weight-based approach contains a less number of genes, and achieves a higher accuracy than other procedures.
With the backdrop of a global ecstasy epidemic, this study sought to examine the trend, correlates, and onset sequence of ecstasy use among adolescents in Taiwan, where a well-established gateway drug such as marijuana is much less popular.
A multistage probability survey of school-attending adolescents in grades 7, 9, 10, and 12, aged 11–19 years, was conducted in 2004, 2005, and 2006. A self-administered anonymous questionnaire elicited response rates ranging from 94.3% to 96.6%. The sample sizes were 18232 respondents in 2004, 17986 in 2005, and 17864 in 2006.
In terms of lifetime prevalence and incidence, ecstasy and ketamine by and large appeared as the first and second commonly used illegal drugs, respectively, among middle (grades 7 and 9) and high school students (grades 10 and 12) during the 3-year survey period; however, this order was reversed in the middle school-aged students starting in 2006. Having sexual experience, tobacco use, and betel nut use were factors consistently associated with the onset of ecstasy use across years. The majority of ecstasy users had been involved in polydrug use, such as the use of ketamine (41.4%–53.5%), marijuana (12.7%–18.7%), and methamphetamine (4.2%–9.5%).
From 2004 to 2006, a decline was noted in the prevalence and incidence rate of ecstasy, a leading illegal drug used by school-attending adolescents in Taiwan since the early 2000s. The emerging ketamine use trend may warrant more attention in the future.
Pneumonia is one of most prevalent infectious diseases worldwide and is associated with considerable mortality. In comparison to general population, schizophrenia patients hospitalized for pneumonia have poorer outcomes. We explored the risk factors of short-term mortality in this population because the information is lacking in the literature.
In a nationwide schizophrenia cohort, derived from the National Health Insurance Research Database in Taiwan, that was hospitalized for pneumonia between 2000 and 2008 (n = 1,741), we identified 141 subjects who died during their hospitalizations or shortly after their discharges. Based on risk-set sampling in a 1∶4 ratio, 468 matched controls were selected from the study cohort (i.e., schizophrenia cohort with pneumonia). Physical illnesses were categorized as pre-existing and incident illnesses that developed after pneumonia respectively. Exposures to medications were categorized by type, duration, and defined daily dose. We used stepwise conditional logistic regression to explore the risk factors for short-term mortality.
Pre-existing arrhythmia was associated with short-term mortality (adjusted risk ratio [RR] = 4.99, p<0.01). Several variables during hospitalization were associated with increased mortality risk, including incident arrhythmia (RR = 7.44, p<0.01), incident heart failure (RR = 5.49, p = 0.0183) and the use of hypoglycemic drugs (RR = 2.32, p<0.01). Furthermore, individual antipsychotic drugs (such as clozapine) known to induce pneumonia were not significantly associated with the risk.
Incident cardiac complications following pneumonia are associated with increased short-term mortality. These findings have broad implications for clinical intervention and future studies are needed to clarify the mechanisms of the risk factors.
We previously reported familial aggregation in flush response to niacin skin patch among schizophrenia patients and their nonpsychotic relatives. However, little is known about whether this abnormal skin response is associated with genetic loading for schizophrenia. This study compared the niacin flush response in subjects from families with only one member affected with schizophrenia (simplex families) with those from families having a sib-pair with schizophrenia (multiplex families). Subjects were patients with schizophrenia and their nonpsychotic first-degree relatives from simplex families (176 probands, 260 parents, and 80 siblings) and multiplex families (311 probands, 180 parents, and 52 siblings) as well as 94 healthy controls. Niacin patches of 3 concentrations (0.001M, 0.01M, and 0.1M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. More attenuated flush response to topical niacin was shown in schizophrenia probands and their relatives from multiplex families than in their counterparts from simplex families, and the differentiation was better revealed using 0.1M concentration of niacin than 0.01M or 0.001M. For the highest concentration of 0.1M and the longest time lag of 15 minutes, a subgroup of probands (23%), parents (27%), and siblings (19%) still exhibited nonflush response. Flush response to niacin skin patch is more impaired in schizophrenia patients and their relatives from families with higher genetic loading for schizophrenia, and this finding has implications for future genetic dissection of schizophrenia.
nicotinic acid; niacin skin test; prostaglandin; vulnerability indicator
Though a reduced flush response to niacin has been found in schizophrenic patients, whether it is a vulnerability indicator to schizophrenia remains little known. We aimed to examine the familial aggregation in niacin flush response among schizophrenic patients and their nonpsychotic relatives. In a sample of 153 schizophrenia probands, 217 parents, 70 siblings, and 94 normal subjects, 3 concentrations (0.001 M, 0.01 M, and 0.1 M) of niacin were applied to the forearm skin and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. Both the heritability for continuous flush scores and the recurrence risk ratios for binary nonflush response in the nonpsychotic relatives of schizophrenic patients were estimated, and ordinal logistic regression analyses of relatives' niacin response on probands' were further conducted to adjust for potential confounders. The greatest heritabilities ranged from 47% (0.01 M at 10 minutes) to 54% (0.1 M at 5 minutes). The risk ratios of 0.01 M at 10 minutes (ranging from 2.60 for using score 1 or less to 5.06 for using score 0 as nonflush) and 5 minutes (1.66 for using score 0 as nonflush) were significantly greater than one. Multiple ordinal logistic regression analyses further revealed that the association between probands and relatives in niacin flush response remained after adjustment for potential confounders, including age, sex, allergy, tobacco smoking, and coffee drinking. These findings provide support for the potential of niacin flush response as a vulnerability indicator to schizophrenia.
nicotinic acid; prostaglandin; heritability; recurrence risk ratio; vulnerability indicator
Illegal drug use and related problems have been emerging as an important public health issue in Taiwan. Via the capture-recapture approach, the present study aimed to offer insights into the size of heroin and methamphetamine male user population in the northern Taiwan during the period from 1999 to 2002.
Annual lists of male subjects were collated from both judiciary and medical systems in Taoyuan County, Taiwan. A total of 2809, 2486, 1661, and 1440 local male illegal drug users aged 15 to 54 years were identified in Taoyuan County from 1999 to 2002, respectively.
An estimated number of 16192, 14532, 16844, and 11783 local male methamphetamine or heroin users were found in each of the four consecutive years in the region. From 1999 to 2002, the annual prevalence rate for heroin use was 0.27% (95% CI = 0.20%, 0.38%), 0.33% (95% CI = 0.25%, 0.44%), 0.63% (95% CI = 0.44%, 0.92%), and 0.72% (95% CI = 0.54%, 0.97%), respectively, suggesting a trend of significant increase (chi-square for linear trend = 1677.76, d.f. = 3, p < 0.0001). In contrast, a decreasing trend was found for methamphetamine (2.38%, 1.91%, 2.47%, and 1.24%), with a modest rebound in 2001. The prevalence rates of illegal drug use for male residents in Taoyuan County were approximately 2–3% during this period, and the scale of problem shows no sign of diminution.
By taking advantage of existing datasets that were incomplete by each alone, the approach of capture-recapture model may be ultimately considered as a tool to estimate the scale of illegal drug use problems. The population of heroin-using males apparently is stably expanding in the northern part of Taiwan in the first years of 21st century.
Apolipoprotein (Apo) A1 is a protective factor for cardiovascular events. This study aimed to perform complex segregation analyses of Apo A1 levels in families of adolescents systematically ascertained from the junior high school students in a rural community. Both siblings and parents of the adolescent probands were recruited for the study. Apo A1 concentrations were measured by turbidimetric immunoassay methods. After adjustment for gender, age, body mass index, smoking and drinking status, residual values of Apo A1 were subjected to subsequent analyses.
Significant mother-father and parent-offspring correlations were found. Commingling analyses indicated that a four-component distribution model was needed to account for the Apo A1 variation. Segregation analysis using regressive models revealed that the best-fit model of Apo A1 was a model of environmental effect plus familial correlation (heritability = 23.9%), in which a significant mother-father correlation existed. Models containing major gene effect could be rejected.
These results suggest that variations of Apo A1 levels in the normal range, especially during adolescence, are likely to be influenced by multiple factors without significant contribution from major genes.
OBJECTIVE: On September 21, 1999, at 1:47 a.m., an earthquake measuring 7.3 on the Richter scale struck the middle Chi-Chi region of Taiwan. The present study examines the response of the public health sector to the earthquake. METHODS: A community needs assessment using modified cluster sampling was performed in shelters of Nantou and Taichung Counties five days after the earthquake struck. Twenty-five temporary medical service systems (TMSSs) conducted surveillance for selected diseases and mortality within one week post-earthquake aided by a buddy system that allowed unaffected counties to provide support to affected counties. RESULTS: The number of cases of acute respiratory infections and acute gastroenteritis in the affected area was higher than that of neighboring unaffected counties in the post-earthquake phase (p<0.001). Earthquake-related deaths were estimated at 2,347 deaths (death rate 116 per 100,000 population); the mean age of the decedents was 49.7 years. No significant difference was observed between males (120/100,000) and females (110/100,000) (risk ratio [RR]=1.09; 95% confidence interval [CI] 0.84, 1.42; p>0.05). The age-adjusted mortality rate was significantly higher in 1999 (odds ratio [OR]=2.11; 95% CI 1.99, 2.24) than in a comparable period in 1998. CONCLUSION: Emergency preparedness must be based on carefully conceived priorities, information, and communications, and improved capabilities must be developed to rapidly implement an emergency public health network. The emergency response to this event-consisting of TMSSs, a buddy system, and a communication system-should be considered in planning for future disaster events in Taiwan.
The purpose of this study was to estimate both cross-sectional sibling recurrence risk ratio (λs) and lifetime λs for the metabolic syndrome and its individual components over time among sibships in the prospectively followed-up cohorts provided by the Genetic Analysis Workshop 13. Five measures included in the operational criteria of the metabolic syndrome by the Adult Treatment Panel III were examined. A method for estimating sibling recurrence risk with correction for complete ascertainment was used to estimate the numerator, and the prevalence in the whole cohort was used as the denominator of λs.
Considerable variability in the λs was found in terms of different time-points for the cross-sectional definition, the times of fulfilling the criterion for lifetime definition, and different components. Obesity and hyperglycemia had the highest cross-sectional λs of the five components. Both components also had the largest slopes in the linear trend of the lifetime λs. However, the magnitudes of the lifetime λs were similar to that of the mean cross-sectional λs, which were <2. The results of nonparametric linkage analysis showed only suggestive evidence of linkage between one marker and lifetime diagnosis of low high-density lipoprotein cholesterol and metabolic syndrome, respectively.
The λs of the metabolic syndrome and its components varies substantially across time, and the λs of lifetime diagnosis was not necessarily larger than that of a cross-sectional diagnosis. The magnitude of λs does not predict well the maximum LOD score of linkage analysis.
Loss of basal forebrain cholinergic neurons is attributable to the proapoptotic signaling induced by nerve growth factor receptor (NGFR) and may link to Alzheimer's disease (AD) risk. Only one study has investigated the association between NGFR polymorphisms and the risk of AD in an Italian population. Type 2 diabetes mellitus (DM) may modify this association based on previous animal and epidemiologic studies.
This was a case-control study in a Chinese population. A total of 264 AD patients were recruited from three teaching hospitals between 2007 to 2010; 389 controls were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency≥5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected from NGFR to test the association between NGFR htSNPs and the risk of AD.
Variant NGFR rs734194 was significantly associated with a decreased risk of AD [GG vs. TT copies: adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.20-0.95]. Seven common haplotypes were identified. Minor haplotype GCGCG was significantly associated with a decreased risk of AD (2 vs. 0 copies: adjusted OR = 0.39, 95% CI = 0.17-0.91). Type 2 DM significantly modified the association between rs2072446, rs741072, and haplotype GCTTG and GTTCG on the risk of AD among ApoE ε4 non-carriers (Pinteraction < 0.05).
Inherited polymorphisms of NGFR were associated with the risk of AD; results were not significant after correction for multiple tests. This association was further modified by the status of type 2 DM.
NGFR; Alzheimer's disease; htSNP; haplotype
Since brain tissue is not readily accessible, a new focus in search of biomarkers for schizophrenia is blood-based expression profiling of non-protein coding genes such as microRNAs (miRNAs), which regulate gene expression by inhibiting the translation of messenger RNAs. This study aimed to identify potential miRNA signature for schizophrenia by comparing genome-wide miRNA expression profiles in patients with schizophrenia vs. healthy controls. A genome-wide miRNA expression profiling was performed using a Taqman array of 365 human miRNAs in the mononuclear leukocytes of a learning set of 30 cases and 30 controls. The discriminating performance of potential biomarkers was validated in an independent testing set of 60 cases and 30 controls. The expression levels of the miRNA signature were then evaluated for their correlation with the patients' clinical symptoms, neurocognitive performances, and neurophysiological functions. A seven-miRNA signature (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) was derived from a supervised classification with internal cross-validation, with an area under the curve (AUC) of receiver operating characteristics of 93%. The putative signature was then validated in the testing set, with an AUC of 85%. Among these miRNAs, miR-34a was differentially expressed between cases and controls in both the learning (P = 0.005) and the testing set (P = 0.002). These miRNAs were differentially correlated with patients' negative symptoms, neurocognitive performance scores, and event-related potentials. The results indicated that the mononuclear leukocyte-based miRNA profiling is a feasible way to identify biomarkers for schizophrenia, and the seven-miRNA signature warrants further investigation.
Accumulated evidences have shown that vascular risk factors, e.g., hypertension, diabetes mellitus and hyperlipidemia, may be related to the risk of dementia. This study investigated the association between genetic polymorphisms of a vascular susceptibility gene, Ninjurin2 (NINJ2), and the risk of dementia, which has not been explored previously.
A total of 275 Alzheimer's disease (AD) patients and 119 vascular dementia (VaD) patients aged 50 or older were recruited from three teaching hospitals from 2007 to 2010. Healthy controls (n = 423) with the same age of cases were recruited from the health checkup and volunteers worked at the hospital during the same time period. Five common (frequency >5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) in NINJ2 were genotyped to test for the association between sequence variants of NINJ2 and dementia risk, and how vascular risk factors modify this association.
Homozygosity of two NINJ2 SNPs was significantly associated with a decreased risk of AD [rs11833579: adjusted odds ratio (AOR) = 0.43; 95% confidence interval (CI) = 0.23–0.80; rs12425791: AOR = 0.33, 95% CI = 0.12–0.96]. Five common haplotypes (cumulative frequency = 97%) were identified. The global test for the association between NINJ2 haplotypes and AD was significant (p = 0.03). Haplotype CAGGA was significantly associated with a decreased risk of AD (AOR = 0.32, 95% CI = 0.11–0.94). No associations were observed for VaD.
Inherited polymorphisms of the vascular susceptibility gene NINJ2 were associated with AD risk.
This study examines the variations in the use of inpatient care that can be explained by travel distance among patients with schizophrenia living in Taiwan. Data were drawn from the Psychiatric Inpatient Medical Claims Database. We used mediation analysis and multilevel analysis to identify associations. Travel distance did not significantly account for lower readmission rates after an index admission, but significantly explained the longer length of stay of an index admission by 9.3 days (P < 0.001, 85% of variation) between remote and non-remote regions. Policies are discussed aimed at reducing the impact of travel distance on rural mental health care through inter-disciplinary collaboration and telepsychiatry.
Schizophrenia; Travel distance; Remote; Length of stay; Readmission