Philip Adams

Genome-wide association study of recurrent early-onset major depressive disorder

A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10−8 approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10−7) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.

Diagnostic interviewing for family studies: Comparing telephone and face-to-face methods for the diagnosis of lifetime psychiatric disorders

Family studies require assessment of large numbers of family members, many of whom are geographically dispersed, live in different time zones, are not available during working hours, live in neighborhoods which are unsafe, or do not wish to have attention drawn to them by the presence of an interviewer in their home. For these reasons, telephone interviews are a potentially valuable and economical method. We present a comparison of results from telephone and face-to-face interviews conducted with 435 relatives of 193 probands from a family study. No significant differences were found between telephone versus face-to-face interviewed relatives in rates of RDC or of DSM-III-R diagnoses. Nor were differences found in the length of interviews; number of family history reports completed; or number of relatives requiring consensus diagnoses due to diagnostic disagreement. We conclude that telephone and face-to-face interviews yielded comparable diagnostic information in this family study and that telephone interviewing is an acceptable and valuable alternative method for the diagnosis of lifetime psychiatric disorder in relatives.

Genomewide Significant Linkage to Recurrent, Early-Onset Major Depressive Disorder on Chromosome 15q

A genome scan was performed on the first phase sample of the Genetics of Recurrent Early-Onset Depression (GenRED) project. The sample consisted of 297 informative families containing 415 independent affected sibling pairs (ASPs), or, counting all possible pairs, 685 informative affected relative pairs (555 ASPs and 130 other pair types). Affected cases had recurrent major depressive disorder (MDD) with onset before age 31 years for probands or age 41 years for other affected relatives; the mean age at onset was 18.5 years, and the mean number of depressive episodes was 7.3. The Center for Inherited Disease Research genotyped 389 microsatellite markers (mean spacing of 9.3 cM). The primary linkage analysis considered allele sharing in all possible affected relative pairs with the use of the Z(lr) statistic computed by the ALLEGRO program. A secondary logistic regression analysis considered the effect of the sex of the pair as a covariate. Genomewide significant linkage was observed on chromosome 15q25.3-26.2 (Zlr=4.14, equivalent LOD = 3.73, empirical genomewide P=.023). The linkage was not sex specific. No other suggestive or significant results were observed in the primary analysis. The secondary analysis produced three regions of suggestive linkage, but these results should be interpreted cautiously because they depended primarily on the small subsample of 42 male-male pairs. Chromosome 15q25.3-26.2 deserves further study as a candidate region for susceptibility to MDD.

Results of a genome-wide genetic screen for panic disorder.

Panic disorder is characterized by spontaneous and recurrent panic attacks, often accompanied by agoraphobia. The results of family, twin, and segregation studies suggest a genetic role in the etiology of the illness. We have genotyped up to 23 families that have a high density of panic disorder with 540 microsatellite DNA markers in a first-pass genomic screen. The thirteen best families (ELOD > 6.0 under the dominant genetic model) have been genotyped with an ordered set of markers encompassing all the autosomes, at an average marker density of 11 cM. Over 110,000 genotypes have been generated on the whole set of families, and the data have been analyzed under both a dominant and a recessive model, and with the program SIBPAIR. No lod scores exceed 2.0 for either parametric model. Two markers give lod scores over 1.0 under the dominant model (chromosomes 1p and 20p), and four do under the recessive model (7p, 17p, 20q, and X/Y). One of these (20p) may be particularly promising. Analysis with SIBPAIR yielded P values equivalent to a lod score of 1.0 or greater (i.e., P < .016, one-sided, uncorrected for multiple tests) for 11 marker loci (2, 7p, 8p, 8q, 9p, 11q, 12q, 16p, 20p and 20q).

Genetics of Recurrent Early-Onset Depression (GenRED): Design and preliminary clinical characteristics of a repository sample for genetic linkage studies

This is an initial report on a six‐site collaborative project, Genetics of Recurrent Early‐Onset Depression (GenRED). This is a study of a large sample of families with recurrent major depressive disorder (DSM‐IV) beginning by the age 30 in probands or 40 in relatives. Evidence suggests that early onset and recurrence of depressive episodes predict substantially increased risk of depression in first‐degree relatives compared with the general population, suggesting that susceptibility genes might be mapped with this phenotype. The projected sample of 800–1,000 affected sibling pairs (ASPs) and other relatives will be studied using genome scan methods. Biological materials and blinded clinical data will be made available through the NIMH cell repository program. The sample should have good‐to‐excellent power to detect a locus associated with a 24% or greater population‐wide increase in risk to siblings. We describe 838 affected individuals from the first 305 families containing 434 independent ASPs, or 613 ASPs counting all possible pairs. The mean age at the onset was 18.5 years, with a mean of 7.3 episodes and longest episode of 655 days. Almost all subjects had experienced at least 4 weeks of depression with five or more additional symptom criteria. Frequencies of symptoms and psychiatric and medical comorbid are provided. Substance use was more common in males, and panic disorder in females. Within pairs of affected siblings, correlations were significant for age at onset, substance abuse/dependence, panic disorder, obsessive‐compulsive disorder and nicotine initiation and persistence. We replicated previously reported associations among comorbid panic disorder and social phobia, chronicity of depression and suicidal behavior. This suggests comparability of our cases to those in earlier large family studies. This dataset should prove useful for genetic studies of a highly familial form of major depressive disorder.

Family psychiatric screening instrument for epidemiologic studies: pilot testing and validation

Family history, a risk factor for psychiatric disorders, is infrequently assessed in epidemiologic studies due to time and cost constraints. We designed a brief computer-scorable instrument, the Family History Screen for Epidemiologic Studies (FHE), which collects a pedigree and screens for 15 DSM-III diagnoses in an informant and in his family members. The FHE was administered to one informant in 77 families in which we had collected pedigrees, interviewed 77 informants and 239 relatives using the Lifetime Anxiety version of the schedule for Affective Disorders and Schizophrenia or the Epidemiologic version of the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, and performed best-estimate diagnoses. We evaluated the accuracy with which the FHE predicted best-estimate diagnoses. For adults reporting on themselves, the FHE demonstrated high levels of sensitivity and specificity for depression (67.4, 75.0) and panic (92.5, 89.2), and low sensitivity and high specificity for substance abuse (33.3, 93.6). For informants reporting on adult relatives, sensitivity was low and specificity was high for depression (35.2, 84.9), panic (20.0, 91.7), and substance abuse (42.1, 93.4). For informants reporting on children, perhaps due to lower prevalence, sensitivity and specificity were poor. The FHE is a good screen for psychiatric disorders in adult informants, but it is not useful for family history. It may be useful in primary care medical settings as a screen for psychiatric history.

Panic disorder is associated with the serotonin transporter gene ( SLC6A4 ) but not the promoter region (5-HTTLPR)

Panic disorder (PD) and social anxiety disorder (SAD) are moderately heritable anxiety disorders. We analyzed five genes, derived from pharmacological or translational mouse models, in a new case–control study of PD and SAD in European Americans: (1) the serotonin transporter (SLC6A4), (2) the serotonin receptor 1A, (3) catechol-O-methyltransferase, (4) a regulator of g-protein signaling and (5) the gastrin-releasing peptide receptor. Cases were interviewed using the schedule for affective disorders and schizophrenia and were required to have a probable or definite lifetime diagnosis of PD (N=179), SAD (161) or both (140), with first onset by age 31 and a family history of anxiety. Final diagnoses were determined using the best estimate procedure, blind to genotyping data. Controls were obtained from the National Institute of Mental Health Human Genetics Initiative; only subjects above 25 years of age who screened negative for all psychiatric symptoms were included (N=470). A total of 45 single nucleotide polymorphisms were successfully genotyped over the five selected genes using Applied Biosystems SNPlex protocol. SLC6A4 provided strong and consistent evidence of association with the PD and PD+SAD groups, with the most significant association in both groups being at rs140701 (χ2=10.72, P=0.001 with PD and χ2=8.59, P=0.003 in the PD+SAD group). This association remained significant after multiple test correction. Those carrying at least one copy of the haplotype A-A-G constructed from rs3794808, rs140701 and rs4583306 have 1.7 times the odds of PD than those without the haplotype (95% confidence interval: 1.2–2.3). The SAD only group did not provide evidence of association, suggesting a PD-driven association. The findings remained after adjustment for age and sex, and there was no evidence that the association was due to population stratification. The promoter region of the gene, 5-HTTLPR, did not provide any evidence of association, regardless of whether analyzed as a triallelic or biallelic locus, nor did any of the other four candidate genes tested. Our findings suggest that the serotonin transporter gene may play a role in PD; however, the findings require replication. Future studies should attend to the entire genetic region rather than the promoter.

Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing.

A study of genome-wide gene expression in major depressive disorder (MDD) was undertaken in a large population-based sample to determine whether altered expression levels of genes and pathways could provide insights into biological mechanisms that are relevant to this disorder. Gene expression studies have the potential to detect changes that may be because of differences in common or rare genomic sequence variation, environmental factors or their interaction. We recruited a European ancestry sample of 463 individuals with recurrent MDD and 459 controls, obtained self-report and semi-structured interview data about psychiatric and medical history and other environmental variables, sequenced RNA from whole blood and genotyped a genome-wide panel of common single-nucleotide polymorphisms. We used analytical methods to identify MDD-related genes and pathways using all of these sources of information. In analyses of association between MDD and expression levels of 13 857 single autosomal genes, accounting for multiple technical, physiological and environmental covariates, a significant excess of low P-values was observed, but there was no significant single-gene association after genome-wide correction. Pathway-based analyses of expression data detected significant association of MDD with increased expression of genes in the interferon α/β signaling pathway. This finding could not be explained by potentially confounding diseases and medications (including antidepressants) or by computationally estimated proportions of white blood cell types. Although cause–effect relationships cannot be determined from these data, the results support the hypothesis that altered immune signaling has a role in the pathogenesis, manifestation, and/or the persistence and progression of MDD.

Recall of childhood psychopathology more than 10 years later.

OBJECTIVE This study investigated recall in a sample of depressed, anxious, and normal children followed up as adults. Strengths of this study were that the length of the retest interval was substantial, follow-up information was collected by blind interviewers, and childhood diagnoses were clearly documented. METHOD The sample consisted of 144 subjects with a childhood diagnosis of depression, 48 with a childhood diagnosis of anxiety, and 128 normal controls. Best-estimate diagnoses assigned at follow-up were compared with childhood primary diagnoses. RESULTS Reliability and sensitivity were fair for major depressive disorder (mean = 0.46 and 50%, respectively) and any depression (mean = 0.57 and 65%, respectively). Reliability and sensitivity were relatively lower for anxiety (mean = 0.32 and 43%, respectively). Sensitivity for any diagnosis was good (mean = 71%). Specificity was good among all diagnostic categories (range = 73%-100%). Results suggest better diagnostic recall for females than for males. Recall was slightly better for subjects who were older than age 12 during their original episode. Age-of-onset reliability was poor (major depressive disorder = 0.22, any depression = 0.22, and any anxiety = -0.13). CONCLUSIONS Recall of any childhood disorder is moderately reliable and accurate. Recall of a specific disorder is less accurate. Depression was more likely to be recalled than anxiety. High specificity suggests that participants were not biased to report disorders not present in childhood.

Segregation analysis of panic disorder

We performed a simple segregation analysis of panic disorder, using 30 two- and three-generation pedigrees. Pedigrees were singly ascertained, either through the Epidemiologic Catchment Area study (seven probands), or as a consecutive series from an anxiety disorders clinic (23 probands). All probands were required to meet DSM-III panic disorder criteria, without comorbid major depression. Relatives (n = 189) were required to meet DSM-III criteria for panic disorder, with or without comorbid major depression. We fitted a single major dominant and a single major recessive model to the data, allowing for an age-of-onset distribution. Under the dominant model, we obtained the following parameter estimates: gene frequency = 0.01; (lifetime) susceptibility for gene carriers = 0.5; susceptibility for non-gene carriers = 0.01. Under the recessive model, we obtained the following parameter estimates: gene frequency = 0.2; susceptibility for gene carriers = 0.7; susceptibility for non-gene carriers = 0.01. The best-fitting dominant and best-fitting recessive models had equally high likelihoods. Discrepancies between our results and earlier reports are discussed, as are implications of these results for linkage analyses of panic disorder.