Po-Hsiu Kuo

The temporal relationship of the onsets of alcohol dependence and major depression : using a genetically informative study design

BACKGROUND Although alcohol dependence (AD) and major depression (MD) are highly co-morbid, their causal relationship is unclear. In this longitudinal study, we used a genetically informative population-based twin sample to examine the age-at-onset distributions and the temporal relationship of AD and MD. METHOD Our sample included 7477 twins, whose diagnoses of AD and MD and age-at-onset information were obtained from structured interviews. Individual-level survival analyses were conducted based on 2603 monozygotic (MZ) twins, and co-twin diagnosis was included in models as an index of familiar liability to AD and MD. RESULTS The age-at-onset distributions of AD and MD differed substantially. Most onsets of AD were in young adulthood, whereas MD had a flatter distribution across age. Most subjects, especially women, had an onset of MD preceding AD. Prior MD significantly affected risk for developing AD, and this risk decreased over time. By contrast, preceding AD had negligible effects on the risk for future MD. Familial risk was transmitted within disorders but there was little evidence of additional familial liability shared across disorders. CONCLUSIONS Risk for developing AD was substantially increased by a prior episode of MD. The association was only partially accounted for by familial factors, providing support for a direct causal effect such as self-medication. The etiologic path from AD to MD was insignificant.

Genomewide Association Analysis Followed by a Replication Study Implicates a Novel Candidate Gene for Neuroticism

CONTEXT Neuroticism is a trait that reflects a tendency toward negative mood states. It has long been linked to internalizing psychiatric conditions, such as anxiety and depression, and it accounts for much of the substantial comorbidity seen between these disorders. OBJECTIVE To identify common genetic variants that affect neuroticism to better understand (the comorbidity between) a broad range of psychiatric disorders and to develop effective treatments. DESIGN, SETTING, AND PARTICIPANTS More than 420,000 genetic markers were tested for their association with neuroticism in a genomewide association study (GWAS). The GWAS sample consisted of 1227 healthy individuals ascertained from a US national sampling frame and available from the National Institute of Mental Health genetics repository. The most promising markers were subsequently tested in a German replication sample comprising 1880 healthy individuals. MAIN OUTCOME MEASURES A strict definition of replication (same marker, same direction of effects, and same measure) combined with a threshold we proposed previously for declaring significance in genetic studies that ensures a mean probability of producing false-positive findings of less than 10%. RESULTS The most promising results in the GWAS and replication samples were single-nucleotide polymorphisms (SNPs) in the gene MAMDC1. These SNPs all tagged the same 2 haplotypes and had P values of 10(-5) to 10(-6) in the GWAS sample and of .006 to .02 in the replication sample. Furthermore, the replication involved the same SNPs and the same direction of effects. In a combined analysis of all data, several SNPs were significant according to the threshold that allows for 10% false-positive findings. CONCLUSIONS The small effect sizes may limit the prognostic, diagnostic, and therapeutic use of SNP markers such as those in MAMDC1. However, the present study demonstrates the potential of a GWAS to discover potentially important pathogenic pathways for which clinically more powerful (bio)markers may eventually be developed.

Genomewide linkage study in the Irish affected sib pair study of alcohol dependence: evidence for a susceptibility region for symptoms of alcohol dependence on chromosome 4.

Alcoholism is a relatively common, chronic, disabling and often treatment-resistant disorder. Evidence from twin and adoption studies indicates a substantial genetic influence, with heritability estimates of 50–60%. We conducted a genome scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Most probands were ascertained through alcoholism treatment settings and were severely affected. Probands, affected siblings and parents were evaluated by structured interview. A 4 cM genome scan was conducted using 474 families of which most (96%) were comprised by affected sib pairs. Nonparametric and quantitative linkage analyses were conducted using DSM-IV alcohol dependence (AD) and number of DSM-IV AD symptoms (ADSX). Quantitative results indicate strong linkage for number of AD criteria to a broad region of chromosome 4, ranging from 4q22 to 4q32 (peak multipoint LOD=4.59, P=2.1 × 10−6, at D4S1611). Follow-up analyses suggest that the linkage may be due to variation in the symptoms of tolerance and out of control drinking. There was evidence of weak linkage (LODs of 1.0–2.0) to several other regions, including 1q44, 13q31, and 22q11 for AD along with 2q37, 9q21, 9q34 and 18p11 for ADSX. The location of the chromosome 4 peak is consistent with results from prior linkage studies and includes the alcohol dehydrogenase gene cluster. The results of this study suggest the importance of genetic variation in chromosome 4 in the etiology and severity of alcoholism in Caucasian populations.

Candidate genes for schizophrenia: a survey of association studies and gene ranking.

More than 500 genes have been reported with positive or negative association with schizophrenia. The wealth of this information, along with the complex nature of psychiatric disorders, provides a challenging but also unique opportunity for the investigation of molecular and cellular mechanisms in schizophrenia. In this study, we performed a comprehensive survey of the published association studies collected in the SchizophreniaGene database. We observed over time a strong trend for increases in the number of published reports, the number of studied genes, and the sample size of the studies. We also examined the studies, genes, and sample sizes in different ethnic populations and the distribution of these association studies and their employed markers among these susceptibility genes. We then selected and ranked candidate genes using a combined odds ratio method. The evaluation of this candidate gene set against sets selected by other methods suggested its utility in follow‐up association studies and in further bioinformatics analysis. We also examined the functional biases of the selected genes.

High Oxidative Stress Is Correlated with Frailty in Elderly Chinese

OBJECTIVES: To evaluate the relationship between oxidative stress and frailty in elderly people.

Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

Objective The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

A comprehensive network and pathway analysis of candidate genes in major depressive disorder

BackgroundNumerous genetic and genomic datasets related to complex diseases have been made available during the last decade. It is now a great challenge to assess such heterogeneous datasets to prioritize disease genes and perform follow up functional analysis and validation. Among complex disease studies, psychiatric disorders such as major depressive disorder (MDD) are especially in need of robust integrative analysis because these diseases are more complex than others, with weak genetic factors at various levels, including genetic markers, transcription (gene expression), epigenetics (methylation), protein, pathways and networks.ResultsIn this study, we proposed a comprehensive analysis framework at the systems level and demonstrated it in MDD using a set of candidate genes that have recently been prioritized based on multiple lines of evidence including association, linkage, gene expression (both human and animal studies), regulatory pathway, and literature search. In the network analysis, we explored the topological characteristics of these genes in the context of the human interactome and compared them with two other complex diseases. The network topological features indicated that MDD is similar to schizophrenia compared to cancer. In the functional analysis, we performed the gene set enrichment analysis for both Gene Ontology categories and canonical pathways. Moreover, we proposed a unique pathway crosstalk approach to examine the dynamic interactions among biological pathways. Our pathway enrichment and crosstalk analyses revealed two unique pathway interaction modules that were significantly enriched with MDD genes. These two modules are neuro-transmission and immune system related, supporting the neuropathology hypothesis of MDD. Finally, we constructed a MDD-specific subnetwork, which recruited novel candidate genes with association signals from a major MDD GWAS dataset.ConclusionsThis study is the first systematic network and pathway analysis of candidate genes in MDD, providing abundant important information about gene interaction and regulation in a major psychiatric disease. The results suggest potential functional components underlying the molecular mechanisms of MDD and, thus, facilitate generation of novel hypotheses in this disease. The systems biology based strategy in this study can be applied to many other complex diseases.

Effects of adjunctive metformin on metabolic traits in nondiabetic clozapine-treated patients with schizophrenia and the effect of metformin discontinuation on body weight: A 24-week, randomized, double-blind, placebo-controlled study

OBJECTIVE Many studies have shown that metformin can decrease body weight and improve metabolic abnormalities in patients with schizophrenia. Whether or not the beneficial effects can be sustained after discontinuation of metformin needs to be evaluated. We conducted a 24-week randomized, double-blind, placebo-controlled study to evaluate the effect of metformin on metabolic features in clozapine-treated patients with schizophrenia and followed their body weight after stopping the intervention for at least 24 weeks. METHOD The study was conducted between September 2008 and July 2011. We recruited patients with DSM-IV diagnosis of schizophrenia or schizoaffective disorder who had been taking clozapine for more than 3 months, were overweight or obese, or fulfilled at least 1 criteria of metabolic syndrome. Eligible patients were randomized to receive metformin 1,500 mg/d or placebo. We followed metabolic features at baseline and at weeks 2, 4, 8, 16, and 24 and rechecked body weight when the patients stopped the trial after at least 24 weeks. RESULTS A total of 55 subjects (28 in the metformin and 27 in the placebo group) were enrolled. There were no significant differences in all baseline characteristics between the 2 groups, except that patients in the metformin group had higher fasting plasma glucose levels (P = .03). After the 24-week intervention, body weight (P < .0001), body mass index (P < .0001), fasting plasma glucose (P < .0001), high-density lipoprotein cholesterol (P = .03), insulin level (P = .01), and homeostasis model assessment index (P = .02) had significant changes in the metformin group. At the end of the intervention, 8 patients (28.57%) lost more than 7% of their body weight in the metformin group. Mean body weight returned to baseline after patients stopped the intervention in the metformin group. CONCLUSIONS Metformin can significantly reduce body weight and reverse metabolic abnormalities in clozapine-treated patients with schizophrenia and preexisting metabolic abnormalities. However, the beneficial effects of metformin on body weight disappeared after discontinuing this medication.

Using a factor mixture modeling approach in alcohol dependence in a general population sample

Alcohol dependence (AD) is a complex and heterogeneous disorder. The identification of more homogeneous subgroups of individuals with drinking problems and the refinement of the diagnostic criteria are inter-related research goals. They have the potential to improve our knowledge of etiology and treatment effects, and to assist in the identification of risk factors or specific genetic factors. Mixture modeling has advantages over traditional modeling that focuses on either the dimensional or categorical latent structure. The mixture modeling combines both latent class and latent trait models, but has not been widely applied in substance use research. The goal of the present study is to assess whether the AD criteria in the population could be better characterized by a continuous dimension, a few discrete subgroups, or a combination of the two. More than seven thousand participants were recruited from the population-based Virginia Twin Registry, and were interviewed to obtain DSM-IV (Diagnostic and Statistical Manual of Mental Disorder, version IV) symptoms and diagnosis of AD. We applied factor analysis, latent class analysis, and factor mixture models for symptom items based on the DSM-IV criteria. Our results showed that a mixture model with 1 factor and 3 classes for both genders fit well. The 3 classes were a non-problem drinking group and severe and moderate drinking problem groups. By contrast, models constrained to conform to DSM-IV diagnostic criteria were rejected by model fitting indices providing empirical evidence for heterogeneity in the AD diagnosis. Classification analysis showed different characteristics across subgroups, including alcohol-caused behavioral problems, comorbid disorders, age at onset for alcohol-related milestones, and personality. Clinically, the expanded classification of AD may aid in identifying suitable treatments, interventions and additional sources of comorbidity based on these more homogenous subgroups of alcohol use problems.

A genome-wide linkage analysis for the personality trait neuroticism in the Irish affected sib pair study of alcohol dependence

Neuroticism is a personality trait which reflects individual differences in emotional stability and vulnerability to stress and anxiety. Consistent evidence shows substantial genetic influences on variation in this trait. The present study seeks to identify regions containing susceptibility loci for neuroticism using a selected sib‐pair sample from Ireland. Using Merlin regress, we conducted a 4 cM whole‐genome linkage analysis on 714 sib‐pairs. Evidence for linkage to neuroticism was found on chromosomes 11p, 12q, and 15q. The highest linkage peak was on 12q at marker D12S1638 with a Lod score of 2.13 (−log p = 2.76, empirical P‐value <0.001). Our data also support gender specific loci for neuroticism, with male specific linkage regions on chromosomes 1, 4, 11, 12, 15, 16, and 22, and female specific linkage regions on chromosomes 2, 4, 9, 12, 13, and 18. Some genome regions reported in the present study replicate findings from previous linkage studies of neuroticism. These results, together with prior studies, indicate several potential regions for quantitative trait loci for neuroticism that warrant further study.