Thomas Lehner

Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression: A Meta-analysis

CONTEXT Substantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression. OBJECTIVE To conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data. DATA SOURCES Search of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis. STUDY SELECTION Criteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, > or = 3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data. DATA EXTRACTION Logistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14,250 participants, 1769 were classified as having depression; 12,481 as not having depression. RESULTS In the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data. CONCLUSION This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.

Exome sequencing and the genetic basis of complex traits

Shamil Sunyaev and colleagues present exome sequencing methods and their applications in studies to identify the genetic basis of human complex traits. They include analyses of the whole-exome sequences of 438 individuals from across several studies.

Candidate Endophenotypes for Genetic Studies of Suicidal Behavior

Twin, adoption, and family studies have established the heritability of suicide attempts and suicide. Identifying specific suicide diathesis-related genes has proven more difficult. As with psychiatric disorders in general, methodological difficulties include complexity of the phenotype for suicidal behavior and distinguishing suicide diathesis-related genes from genes associated with mood disorders and other suicide-associated psychiatric illness. Adopting an endophenotype approach involving identification of genes associated with heritable intermediate phenotypes, including biological and/or behavioral markers more proximal to genes, is an approach being used for other psychiatric disorders. Therefore, a workshop convened by the American Foundation for Suicide Prevention, the Department of Psychiatry at Columbia University, and the National Institute of Mental Health sought to identify potential target endophenotypes for genetic studies of suicidal behavior. The most promising endophenotypes were trait aggression/impulsivity, early-onset major depression, neurocognitive function, and cortisol social stress response. Other candidate endophenotypes requiring further investigation include serotonergic neurotransmission, second messenger systems, and borderline personality disorder traits.

A framework for interpreting genome-wide association studies of psychiatric disorders

Genome-wide association studies (GWAS) have yielded a plethora of new findings in the past 3 years. By early 2009, GWAS on 47 samples of subjects with attention-deficit hyperactivity disorder, autism, bipolar disorder, major depressive disorder and schizophrenia will be completed. Taken together, these GWAS constitute the largest biological experiment ever conducted in psychiatry (59 000 independent cases and controls, 7700 family trios and >40 billion genotypes). We know that GWAS can work, and the question now is whether it will work for psychiatric disorders. In this review, we describe these studies, the Psychiatric GWAS Consortium for meta-analyses of these data, and provide a logical framework for interpretation of some of the conceivable outcomes.

The Netherlands twin register biobank: A resource for genetic epidemiological studies

In 2004 the Netherlands Twin Register (NTR) started a large scale biological sample collection in twin families to create a resource for genetic studies on health, lifestyle and personality. Between January 2004 and July 2008, adult participants from NTR research projects were invited into the study. During a home visit between 7:00 and 10:00 am, fasting blood and morning urine samples were collected. Fertile women were bled on day 2-4 of the menstrual cycle, or in their pill-free week. Biological samples were collected for DNA isolation, gene expression studies, creation of cell lines and for biomarker assessment. At the time of blood sampling, additional phenotypic information concerning health, medication use, body composition and smoking was collected. Of the participants contacted, 69% participated. Blood and urine samples were collected in 9,530 participants (63% female, average age 44.4 (SD 15.5) years) from 3,477 families. Lipid profile, glucose, insulin, HbA1c, haematology, CRP, fibrinogen, liver enzymes and creatinine have been assessed. Longitudinal survey data on health, personality and lifestyle are currently available for 90% of all participants. Genome-wide SNP data are available for 3,524 participants, with additional genotyping ongoing. The NTR biobank, combined with the extensive phenotypic information available within the NTR, provides a valuable resource for the study of genetic determinants of individual differences in mental and physical health. It offers opportunities for DNA-based and gene expression studies as well as for future metabolomic and proteomic projects.

The Autism Sequencing Consortium: Large-Scale, High-Throughput Sequencing in Autism Spectrum Disorders

Research during the past decade has seen significant progress in the understanding of the genetic architecture of autism spectrum disorders (ASDs), with gene discovery accelerating as the characterization of genomic variation has become increasingly comprehensive. At the same time, this research has highlighted ongoing challenges. Here we address the enormous impact of high-throughput sequencing (HTS) on ASD gene discovery, outline a consensus view for leveraging this technology, and describe a large multisite collaboration developed to accomplish these goals. Similar approaches could prove effective for severe neurodevelopmental disorders more broadly.

The PsychENCODE project

Recent research on disparate psychiatric disorders has implicated rare variants in genes involved in global gene regulation and chromatin modification, as well as many common variants located primarily in regulatory regions of the genome. Understanding precisely how these variants contribute to disease will require a deeper appreciation for the mechanisms of gene regulation in the developing and adult human brain. The PsychENCODE project aims to produce a public resource of multidimensional genomic data using tissue- and cell type–specific samples from approximately 1,000 phenotypically well-characterized, high-quality healthy and disease-affected human post-mortem brains, as well as functionally characterize disease-associated regulatory elements and variants in model systems. We are beginning with a focus on autism spectrum disorder, bipolar disorder and schizophrenia, and expect that this knowledge will apply to a wide variety of psychiatric disorders. This paper outlines the motivation and design of PsychENCODE.

Epidemiology and factor analysis of obesity, type II diabetes, hypertension, and dyslipidemia (syndrome X) on the Island of Kosrae, Federated States of Micronesia.

Objectives: Obesity, type II diabetes, hypertension, and dyslipidemia are major causes of morbidity and mortality throughout the world. Though these disorders often cluster in individuals and families and are collectively known as syndrome X, the basis for this aggregation is not well understood. To further understand the pathogenesis of syndrome X, a comprehensive epidemiological study was undertaken on the Pacific Island of Kosrae, Federated States of Micronesia (FSM). Methods: The entire adult (>20 years of age) population of Kosrae underwent a clinical evaluation that included a questionnaire that noted the participants’ sex, family data including listing of biological parents, siblings, and children, smoking status, village of residence, age and health status. The medical evaluation included: anthropometric measures (weight, height, waist, hip), serum chemistries (leptin, fasting blood sugar (FBS), insulin, total cholesterol (TC), triglycerides (TG), and apolipoproteins B and A-I (apo B and apo A-I) and blood pressure (BP) measurements. Results: Obesity (BMI ≥35) was found in 24%, diabetes (FBS ≥126 or 2-hour oral glucose tolerance test ≥200) in 12%, hypertension (SBP ≥140 or DBP ≥90) in 17%, and dyslipidemia (TC ≥240 or TG ≥200 or apo B ≥120 or apo A-I ≤88) in 20% of the population. Significant covariate effects after multivariate analysis were as follows: sex affected the frequency of all four disorders, parity affected the frequency of dyslipidemia, smoking affected the frequency of obesity and diabetes, village of residence affected the frequency of obesity, hypertension, and dyslipidemia, and age affected the frequency of all four disorders. Factor analysis identified four independent factors that explained 73% of the total variance of the entire data set: factor 1 (weight, waist, leptin, insulin, and TG), factor 2 (TC, TG, apo B, apo A-I, and insulin), factor 3 (systolic and diastolic BP, FBS, waist and weight), and factor 4 (apo A-I, TG, leptin, and weight). Conclusions: This population-based study on the Island of Kosrae suggests that syndrome X is a composite of 4 independent factors: obesity with diabetes and hypertriglyceridemia, combined hyperlipidemia with diabetes, hypertension with obesity and diabetes, and increased HDL-low TG with thinness and high leptin. Further studies to identify the genetic components of these factors as well as the individual traits are under way.

Hereditary febrile seizures: Phenotype and evidence for a chromosome 19p locus

The occurrence of febrile seizures (FSs) in large autosomal dominant FS kindreds makes possible accurate delineation of the pure clinical phenotype of hereditary FS among secondary FS cases, and the identification of gene loci causing susceptibility to FS. Recently FS gene loci on chromosomes 8 and 19 were identified. We studied the phenotype of FS in four large families in which FS is an autosomal dominant trait. Among 30 affected secondary FS cases, mean age of onset was 16.3 months (range 4 to 36 months), sex ratio was equal, and 43% were complex (13 of 30). Among these 30 secondary FS cases, the mean number of FSs was 2.1, half had only a single FS, and none had afebrile seizures. Penetrance was 0.67, approximately the same as in our previous larger group of 40 multicase FS families (0.64). The occurrence of DPT encephalopathy in a sib of a patient with FS raises the possibility that these two etiologies are related. Linkage studies showed that one of the four families (Family 1) was linked to chromosome 19p markers, none of the families was linked to chromosome 8q markers, and the largest FS family (Kindred 6) was unlinked to either 19p or 8q markers, supporting the hypothesis of genetic heterogeneity for FS.

Association of genetic variants in the HDL receptor, SR-B1, with abnormal lipids in women with coronary artery disease

Plasma lipid concentrations are complex traits having both environmental and genetic determinants. About half of the variation in HDL-C and TG may be genetic1–3 with the same genes possibly accounting for the correlated traits of LDL particle size, TG, and HDL-C.4 A number of variants in candidate genes have been implicated in the regulation of plasma lipid levels.5 In addition, genome scans have identified chromosomal regions with suggestive linkage to the TG:HDL-C ratio and other lipid parameters.6,7 Nonetheless, much of the genetic variability in HDL-C and TG levels remains unexplained. Decreased HDL cholesterol (HDL-C) and raised triglyceride (TG) levels are well known risk factors for the development of coronary artery disease (CAD) and atherosclerosis.8 Plasma TG and HDL-C levels are highly correlated, but there is some evidence that they may exert independent effects on coronary disease risk.9 Indeed, the simultaneous use of both may more accurately predict risk of coronary disease. Among patients with low HDL-C, risk of CAD was more than doubled in those with concurrent high TG compared to those with low TG levels in both the PROCAM10 and Helsinki Heart studies.11 Furthermore, the ratio of TG:HDL-C has been shown to correlate with LDL particle size12 and is a powerful predictor of future myocardial infarction.13 The scavenger receptor class B type 1, SR-B1, is a key component in the reverse cholesterol transport pathway where it binds HDL-C with high affinity and is involved in the selective transfer of lipids from HDL-C.14,15 It is expressed primarily in liver and non-placental steroidogenic tissues and mediates selective cholesterol uptake by a mechanism distinct from the classical low density lipoprotein cholesterol (LDL-C) receptor pathway.16 Previous studies17,18 have found single nucleotide polymorphisms (SNPs) in the gene …