Gene expression biomarkers of response to citalopram treatment in major depressive disorder.

There is significant variability in antidepressant treatment outcome, with ∼30-40% of patients with major depressive disorder (MDD) not presenting with adequate response even following several trials. To identify potential biomarkers of response, we investigated peripheral gene expression patterns of response to antidepressant treatment in MDD. We did this using Affymetrix HG-U133 Plus2 microarrays in blood samples, from untreated individuals with MDD (N=63) ascertained at a community outpatient clinic, pre and post 8-week treatment with citalopram, and used a regression model to assess the impact of gene expression differences on antidepressant response. We carried out technical validation of significant probesets by quantitative reverse transcriptase PCR and conducted central nervous system follow-up of the most significant result in post-mortem brain samples from 15 subjects who died during a current MDD episode and 11 sudden-death controls. A total of 32 probesets were differentially expressed according to response to citalopram treatment following false discovery rate correction. Interferon regulatory factor 7 (IRF7) was the most significant differentially expressed gene and its expression was upregulated by citalopram treatment in individuals who responded to treatment. We found these results to be concordant with our observation of decreased expression of IRF7 in the prefrontal cortex of MDDs with negative toxicological evidence for antidepressant treatment at the time of death. These findings point to IRF7 as a gene of interest in studies investigating genomic factors associated with antidepressant response.

Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene-environment study.

To investigate similarities and differences in the serotonergic diathesis for mood disorders and suicide attempts, we conducted a study in a cohort followed longitudinally for 22 years. A total of 1255 members of this cohort, which is representative of the French-speaking population of Quebec, were investigated. Main outcome measures included (1) mood disorders (bipolar disorder and major depression) and suicide attempts by early adulthood; (2) odds ratios and probabilities associated with 143 single nucleotide polymorphisms in 11 serotonergic genes, acting directly or as moderators in gene-environment interactions with childhood sexual or childhood physical abuse (CPA), and in gene-gene interactions; (3) regression coefficients for putative endophenotypes for mood disorders (childhood anxiousness) and suicide attempts (childhood disruptiveness). Five genes showed significant adjusted effects (HTR2A, TPH1, HTR5A, SLC6A4 and HTR1A). Of these, HTR2A variation influenced both suicide attempts and mood disorders, although through different mechanisms. In suicide attempts, HTR2A variants (rs6561333, rs7997012 and rs1885884) were involved through interactions with histories of sexual and physical abuse whereas in mood disorders through one main effect (rs9316235). In terms of phenotype-specific contributions, TPH1 variation (rs10488683) was relevant only in the diathesis for suicide attempts. Three genes contributed exclusively to mood disorders, one through a main effect (HTR5A (rs1657268)) and two through gene-environment interactions with CPA (HTR1A (rs878567) and SLC6A4 (rs3794808)). Childhood anxiousness did not mediate the effects of HTR2A and HTR5A on mood disorders, nor did childhood disruptiveness mediate the effects of TPH1 on suicide attempts. Of the serotonergic genes implicated in mood disorders and suicidal behaviors, four exhibited phenotype-specific effects, suggesting that despite their high concordance and common genetic determinants, suicide attempts and mood disorders may also have partially independent etiological pathways. To identify where these pathways diverge, we need to understand the differential, phenotype-specific gene-environment interactions such as the ones observed in the present study, using suitably powered samples.

Differential RNA expression between schizophrenic patients and controls of the dystrobrevin binding protein 1 and neuregulin 1 genes in immortalized lymphocytes.

The dystrobrevin binding protein 1 (DTNBP1) and neuregulin 1 (NRG1) genes have been related to schizophrenia (SZ) and bipolar disorder (BP) by several whole-genome linkage and associations studies. Few expression studies in post-mortem brains have also reported a lower or a higher expression of DTNBP1 and NRG1, respectively, in SZ. Since the difficulty to access post-mortem brains, we evaluated RNA expression of DTNBP1 and NRG1 in immortalized lymphocytes of SZ patients and unrelated-family controls. An antipsychotic stimulation was also used to challenge the genetic background of the subjects and enhance differential expression. Immortalized lymphocytes of twelve SZ and twelve controls were grown individually in the presence or not of the antipsychotic olanzapine (Zyprexa; EliLilly). RNA was extracted and pooled in four groups of three SZ and four groups of three controls, and used to probe Agilent 18K microchips. Mean gene expression values were contrasted between SZ and control groups using a T-test. For DTNBP1, RNA expression was lower in SZ than in controls before (-28%; p=0.02) and after (-30%; p=0.01) olanzapine stimulation. Similarly, NRG1 GGF2 isoform showed a lower expression in SZ before (-29%; p=0.04) and after (-33%; p=0.02) olanzapine stimulation. In contrast, NRG1 GGF isoform showed no significant difference between SZ and controls (-7%; p=0.61, +3%; p=0.86, respectively), but was slightly repressed by olanzapine in controls (-8%; p=0.008) but not in SZ (+1%; p=0.91). These results are in agreement with those observed in post-mortem brain when the isoforms involved are considered.

Clinical diagnoses in young offspring from eastern Québec multigenerational families densely affected by schizophrenia or bipolar disorder.

OBJECTIVE: The follow-up since 1989 of a large sample of multigenerational families of eastern Québec that are densely affected by schizophrenia (SZ) or bipolar disorder (BP) has permitted to look at the rates of DSM diagnoses in the young offspring of a SZ parent (HRSZ) and of a BP parent (HRBP) who had an extremely loaded family history. METHOD: The sample (average age of 17.5, SD 4.5) consisted of 54 high-risk offspring (HR) having one parent affected by a DSM-IV SZ or BP. The parents descended from 21 multigenerational families that constitute a quasi-total sample of such kindred in eastern Québec. The HRs were administered a lifetime best estimate DSM-IV diagnosis. RESULTS: We observed that the rates, the diversity of diagnoses, the high comorbidity, the severity and the age of onset of the clinical diagnoses tended to be similar with those already reported in the offspring of affected parents with a low familial loading. Although the sample size was small, HRSZ and HRBP also tended to show similarities in their clinical status. CONCLUSION: Overall, taking into account methodological limitations, the observation early in life of some shared characteristics among HRSZ and HRBP in terms of non-psychotic diagnosis may be congruent with the accumulating evidence that several phenotypic features are shared in adulthood by the two major psychoses.

Possible association of the pro-melanin-concentrating hormone gene with a greater body mass index as a side effect of the antipsychotic olanzapine.

Following our report of a linkage at 12q24 with a phenotype of obesity under antipsychotics, we tested the pro-melanin-concentrating hormone (PMCH) candidate gene for a possible association in humans with the body mass index (BMI; kg/m2) in unrelated schizophrenic patients (SZ) receiving antipsychotics (N = 300) and in controls (CTL; N = 150). Subjects were classified in obese (OB) (BMI > or = 30 kg/m2), overweight (25 < or = BMI < 30 kg/m2), and normal weight (BMI < 25 kg/m2) groups. Single nucleotide polymorphisms (SNP) rs7973796 and rs11111201, located 5' at -4.5 kb and 3' at +1.8 kb, respectively, of PMCH were genotyped. Interaction effects of genotypes and antipsychotic treatment on BMI were tested in a covariance analysis with age and gender as covariates. Interaction effects on the prevalence of obesity were tested in a logistic regression analysis. For subjects under 50 years, the effect of the rs7973796 genotype on BMI differed between the SZ patients taking olanzapine and CTL group (interaction P = 0.025). Olanzapine-treated SZ patients carrying the ancestral homozygote genotype showed a higher BMI for rs7973796 (P = 0.016 with the LSMeans t-test) than the variant homozygotes. Accordingly, the ORs for obesity associated with rs7973796 genotypes differed in the SZ patients taking olanzapine compared to the CTL group (interaction P = 0.0094). The G allele was associated with an increase in the odds of obesity in SZ patients taking olanzapine. No association was observed for those over 50 years, or for rs11111201. These results suggest that the common allele of PMCH rs7973796 may be associated with a greater BMI in olanzapine-treated SZ patients.

Epidemiology of insomnia: prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors.

BACKGROUND AND PURPOSE: To estimate the prevalence of insomnia symptoms and syndrome in the general population, describe the types of self-help treatments and consultations initiated for insomnia, and examine help-seeking determinants. PATIENTS AND METHODS: A randomly selected sample of 2001 French-speaking adults from the province of Quebec (Canada) responded to a telephone survey about sleep, insomnia, and its treatments. RESULTS: Of the total sample, 25.3% were dissatisfied with their sleep, 29.9% reported insomnia symptoms, and 9.5% met criteria for an insomnia syndrome. Thirteen percent of the respondents had consulted a healthcare provider specifically for insomnia in their lifetime, with general practitioners being the most frequently consulted. Daytime fatigue (48%), psychological distress (40%), and physical discomfort (22%) were the main determinants prompting individuals with insomnia to seek treatment. Of the total sample, 15% had used at least once herbal/dietary products to facilitate sleep and 11% had used prescribed sleep medications in the year preceding the survey. Other self-help strategies employed to facilitate sleep included reading, listening to music, and relaxation. CONCLUSIONS: These findings confirm the high prevalence of insomnia in the general population. While few insomnia sufferers seek professional consultations, many individuals initiate self-help treatments, particularly when daytime impairments such as fatigue become more noticeable. Improved knowledge of the determinants of help-seeking behaviors could guide the development of effective public health prevention and intervention programs to promote healthy sleep.

Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families.

The goal of this study was to identify susceptibility loci shared by schizophrenia (SZ) and bipolar disorder (BP), or specific to each. To this end, we performed a dense genome scan in a first sample of 21 multigenerational families of Eastern Quebec affected by SZ, BP or both (N=480 family members). This probably constitutes the first genome scan of SZ and BP that used the same ascertainment, statistical and molecular methods for the concurrent study of the two disorders. We genotyped 607 microsatellite markers of which 350 were spaced by 10 cM and 257 others were follow-up markers in positive regions at the 10 cM scan. Lander and Kruglyak thresholds were conservatively adjusted for multiple testings. We maximized the lod scores (mod score) over eight combinations (2 phenotype severity levels x 2 models of transmission x 2 analyses, affected/unaffected vs affected-only). We observed five genomewide significant linkages with mod score >4.0: three for BP (15q11.1, 16p12.3, 18q12-q21) and two for the shared phenotype, that is, the common locus (CL) phenotype (15q26,18q12-q21). Nine mod scores exceeded the suggestive threshold of 2.6: three for BP (3q21, 10p13, 12q23), three for SZ (6p22, 13q13, 18q21) and three for the CL phenotype (2q12.3, 13q14, 16p13). Mod scores >1.9 might represent confirmatory linkages of formerly reported genomewide significant findings such as our finding in 6p22.3 for SZ. Several regions appeared to be shared by SZ and BP. One linkage signal (15q26) appeared novel, whereas others overlapped formerly reported susceptibility regions. Despite the methodological limitations we raised, our data support the following trends: (i) results from several genome scans of SZ and BP in different populations tend to converge in specific genomic regions and (ii) some of these susceptibility regions may be shared by SZ and BP, whereas others may be specific to each. The present results support the relevance of investigating concurrently SZ and BP within the same study and have implications for the modelling of genetic effects.

A genome wide linkage study of obesity as secondary effect of antipsychotics in multigenerational families of eastern Quebec affected by psychoses.

Antipsychotics can induce in schizophrenic (SZ) and bipolar disorder (BP) patients serious body weight changes that increase risk for noncompliance to medication, and risk for cardiovascular diseases and diabetes. A genetic origin for this susceptibility to weight changes has been hypothesized because only a proportion of treated patients are affected, the degree of affection differing also in rates and magnitudes. In a first genome scan on obesity under antipsychotics in SZ and BP, we analyzed 21 multigenerational kindreds (508 family members) including several patients treated for a minimum of 3 years mainly with haloperidol or chlopromazine. Obesity was defined from medical files and was shown to be 2.5 times more frequent in patients treated with antipsychotics than in untreated family members (30 vs 12%). The nine pedigrees that showed at least two occurrences of obesity under antipsychotics were submitted to model-based linkage analyses. We observed a suggestive linkage with a multipoint Lod score (MLS) of 2.74 at 12q24. This linkage finding vanished when we used as phenotypes, obesity unrelated to antipsychotics, and when we used SZ or BP. This suggests that this positive linkage result with obesity is specific to the use of antipsychotics. A potential candidate gene for this linkage is the pro-melanin-concentrating hormone (PMCH) gene located at less then 1 cM of the linkage. PMCH encodes a neuropeptide involved in the control of food intake, energy expenditure, and in anxiety/depression. This first genome scan targeting the obesity side effect of antipsychotics identified 12q24 as a susceptibility region.

A search for specific and common susceptibility loci for schizophrenia and bipolar disorder: a linkage study in 13 target chromosomes.

We report the first stage of a genome scan of schizophrenia (SZ) and bipolar disorder (BP) covering 18 candidate chromosomal areas. In addition to testing susceptibility loci that are specific to each disorder, we tested the hypothesis that some susceptibility loci might be common to both disorders. A total of 480 individuals from 21 multigenerational pedigrees of Eastern Québec were evaluated by means of a consensus best-estimate diagnosis made blind to diagnoses in relatives and were genotyped with 220 microsatellite markers. Two-point and multipoint model-based linkage analyses were performed and mod scores (Z, for max Z(max)) are reported. The strongest linkage signals were detected at D18S1145 (in 18q12; Z = 4.03) for BP, and at D6S334 (in 6p 22-24; Z(het) = 3.47; alpha = 0.66) for SZ. Three other chromosomal areas (3q, 10p, and 21q) yielded linkage signals. Chromosomes 3p, 4p, 5p, 5q, 6q, 8p, 9q, 11q, 11p, 12q, 13q, 18p and 22q showed no evidence of linkage. The 18q12 results met the Lander and Kruglyak (1995) criterion for a genome-wide significant linkage and suggested that this susceptibility region may be shared by SZ and BP. The 6p finding provided confirmatory evidence of linkage for SZ. Our results suggest that both specific and common susceptibility loci must be searched for SZ and BP.

Male gender is associated with deficit schizophrenia: a meta-analysis.

An association between deficit schizophrenia and male gender could be expected, since male schizophrenic subjects have been repeatedly found more severe than females on several dimensions of severity. Surprisingly, very few studies have confirmed such an association. We performed a more definitive test of this association using a meta-analysis. A pooled odds ratio was computed based on the 23 studies that reported the gender ratio in deficit vs. non-deficit schizophrenia. We tested for the heterogeneity of the association and examined the potential impact of the sampling method, the method used to assess the deficit syndrome, the breadth of diagnoses included and the mean duration of illness. A highly significant association between male gender and deficit schizophrenia was observed (pooled odds ratio=1.75). There was no definitive evidence that differences across studies in sampling methods, breadth of diagnoses included, mean duration of illness and methods to assess the deficit syndrome affected the strength of the association. However, the studies using the "Proxy Deficit Syndrome" method to assess the deficit syndrome yielded qualitatively weaker evidence. This significant association between male gender and deficit schizophrenia may reflect the influence of a gender related factor (e.g. sexual hormones) or gender differences in the liability to different etiologies of schizophrenia. The role of gender as a potential confounder must be closely examined in studies comparing deficit and non-deficit SZ.

[Introduction to genetic psychiatry: progress in uncovering genetic susceptibility to psychiatric disorders]. / Introduction à la psychiatrie génétique: progrès vers la découverte des gènes de susceptibilité aux troubles psychiatriques.

The recent progress in human genetics suggests major benefits in clinical practice, including psychiatry. This article introduces the research methodology used in psychiatric genetics and explains how it is applied, for a better understanding of the challenges facing psychiatric genetics and the strategies being used to overcome them. We will review the evidence of genetic factors in psychiatric disorder etiology as well as the specificity or non-specificity of their expression. We will discuss problems associated with the approximate nature of diagnostic methods, the incomplete penetrance and the genetic heterogeneity of psychiatric disorders, the presence of phenocopies and our uncertainty concerning the mode of inheritance of psychiatric disorders. Finally, we will provide an overview of the most promising results and set out priorities for future studies.

Subtyping schizophrenia according to outcome or severity: a search for homogeneous subgroups.

There is a growing consensus that current definitions of schizophrenia (SZ) include different disorders, or else different dimensions underlain by different pathophysiologies. This article reviews the evidence for the validity of three novel strategies to subtype SZ according to outcome or severity (deficit vs. nondeficit, Kraepelinian vs. non-Kraepelinian, congenital vs. adult-onset). Medline and bibliographies were used to locate articles. The methodology of the studies was reviewed, and their results were grouped according to seven validating criteria. Several differences were found between subtypes, particularly for the deficit/nondeficit subtypes. However, for most of these differences, replications have yet to be undertaken. Important indicators of etiology from the environmental risk factors and genetic domains have received very little attention. These three subtyping strategies represent promising attempts to address the etiologic heterogeneity of SZ. However, one cannot conclude whether these strategies identify etiologically distinct SZ subgroups. We propose ten methodological and conceptual recommendations for future studies aimed at the identification of valid SZ subtypes according to outcome or severity.

Ascertainment and anticipation in family studies.

Many human diseases show anticipation; that is, disease occurs earlier (or with greater severity) in successive generations. In a computer simulation, we assessed the degree of anticipation that one would expect to see in two-generation breast cancer families. Under reasonable assumed distributions for age at cancer onset, number of children, and mortality, we find a consistent earlier mean age at diagnosis in daughters than in mothers, but the same mean age at diagnosis in affected aunts and nieces. We compare these results with published pedigree data for familial breast cancer that show substantial anticipation in affected daughters compared to their mothers. We find that at least some anticipation is expected in human disease families even when the disease is stable and families are ascertained without obvious sampling bias. We further demonstrate that such anticipation is reduced when comparing affected children to the parents' affected siblings.

Prolongation of brainstem auditory-evoked responses in autistic probands and their unaffected relatives.

BACKGROUND: Brain function, as indexed by brain electrical activity, is heritable in humans, and it may be impaired in autism. Autism also has strong genetic determinants, and like all major psychiatric disorders, its complex clinical phenotype renders genetic studies difficult. Innovative strategies focused on alternative biological phenotypes are needed. METHODS: The early brain auditory-evoked response was assessed in 73 autistic probands and 251 relatives who were compared with 521 normal controls. RESULTS: We first confirmed in the autistic probands the presence of a slowing in nerve conduction in the auditory system as expressed by the prolongation of early brain auditory-evoked response under the form of I-III interpeak latencies (IPLs). Furthermore, we observed the same I-III IPL prolongation in the unaffected first degree relatives of the autistic probands compared with controls. Despite clear evidence of a coaggregation of autism and I-III IPL prolongation in families, the IPLs did not seem to be the sole liability factor for autism as suggested by the observation of 52% of families in which the autistic proband and relatives showed normal IPLs. CONCLUSION: A prolongation of the early brain auditory-evoked response IPLs may be a marker for one of several deficits underlying autism and deserves further analysis as a potential alternative phenotype for the disorder.

Significant linkage for Tourette syndrome in a large French Canadian family.

Family and twin studies provide strong evidence that genetic factors are involved in the transmission of Gilles de la Tourette syndrome (TS) and related psychiatric disorders. To detect the underlying susceptibility gene(s) for TS, we performed linkage analysis in one large French Canadian family (127 members) from the Charlevoix region, in which 20 family members were definitely affected by TS and 20 others showed related tic disorders. Using model-based linkage analysis, we observed a LOD score of 3.24 on chromosome 11 (11q23). This result was obtained in a multipoint approach involving marker D11S1377, the marker for which significant linkage disequilibrium with TS recently has been detected in an Afrikaner population. Altogether, 25 markers were studied, and, for level of significance, we derived a criterion that took into account the multiple testing arising from the use of three phenotype definitions and three modes of inheritance, a procedure that yielded a LOD score of 3.18. Hence, even after adjustment for multiple testing, the present study shows statistically significant evidence for genetic linkage with TS.

Longitudinal comparative study of risperidone and conventional neuroleptics for treating patients with schizophrenia. The Quebec Schizophrenia Study Group.

This study compared the long-term (12 months) effectiveness of risperidone (RP) with that of conventional neuroleptics (CNs) in a population with chronic schizophrenia who had shown suboptimal response to CNs. A randomized, open, parallel, multicenter design was used. One hundred eighty-four subjects meeting DSM-IV criteria for schizophrenia were randomly assigned to receive either RP or a CN, and 165 of them completed the follow-up. Outcome measures were taken at 3, 6, and 12 months and included the Positive and Negative Syndrome Scale (PANSS) and the Extrapyramidal Symptom Rating Scale. Within this 12-month follow-up, RP was found to be superior to CNs in terms of both the average change in score from baseline on the PANSS (p = 0.006) and the proportion of good responders (as defined by a 20% decrease in total PANSS scores;p = 0.03). For positive symptoms, the effectiveness of the RP treatment tended to increase over time. At 12 months, the percentage of good responders in the RP group was twice as large as that in the CN group (30% vs. 15%;p = 0.03). The superiority of RP over CNs was constant over the three dose categories. In both the RP and the CN groups, the maximum decrease in psychopathology was achieved with the lowest dose range. A worsening of akathisia was less frequent in subjects receiving RP than in those receiving CNs (p = 0.02). In conclusion, this study showed that, compared with CNs, RP is beneficial in the treatment of patients with chronic schizophrenia and that some of these benefits may appear only after longer-term treatment.

Anticipation in schizophrenia and bipolar disorder controlling for an information bias.

Anticipation was investigated in schizophrenia (SZ) and bipolar disorder (BP) while addressing several biases in 18 large families (154 subjects) from Eastern Québec densely affected by SZ, BP, or both over three generations. In particular, we controlled for an information bias using a measure of quality and quantity of clinical information (QOI) concerning the subjects' illness. Otherwise, spurious anticipation could have arisen because we found that QOI varied with the generations as well as with the severity of illness. Although anticipation was investigated separately for SZ and BP, both disorders were also included in one analysis that tested anticipation under the unitary hypothesis that the SZ and the BP spectrums represent a continuum of severity of the same disease. Age of onset (AOO) and five indices of severity were tested for anticipation. Two statistics were used: the difference in the mean AOO or severity between two successive generations, and the mean difference in parent-offspring pairs (POP). The study led to four main findings: 1) the choice of the statistics greatly influenced the results, POP yielding systematically greater biased estimates; 2) for SZ and BP, the evidence for anticipation with the five severity indices vanished after controlling for QOI; 3) as regards AOO a decrease of 8.6 years, p = 0.0001, and 5.3 years, p = 0.009 in AOO was found for SZ between Generations 1-2, and 2-3, respectively, despite controlling for QOI and addressing all biases; and 4) conversely for BP, anticipation with AOO may be due to censoring. Findings suggest that future anticipation studies should also control for QOI. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:61-68, 2000.

Exploring the impact of extended phenotype in stratified samples.

We have performed initial nonparametric sib-pair genome scans in the early (N = 52) and late (N = 53) onset subgroups of the COGA pedigrees, stratified near the median value of pedigree mean age of onset for ALDX1 diagnosis of alcoholism. Because the early group contained a higher proportion of smokers, traits of alcoholism, smoking, and addiction (defined as either alcoholism or smoking) were examined. Subgroups and phenotypic definitions influenced initial linkage results, corrected for the number of analyzed traits. Evidence for linkage to the ALDX1 alcoholism phenotype at the ADH3 functional candidate gene was increased in the late onset subgroup (Bonferroni corrected significance level < 0.002), as compared with the unstratified sample that replicated COGA linkage obtained in the same analysis; there was no evidence for linkage at this locus in the early onset subgroup. The theoretical implication of this result is that the loss of power due to contracting sample size through stratification may in some cases be more than offset by extraction of a more homogeneous subgroup from the etiologically complex trait.

Evidence of linkage in subtypes of alcoholism.

We believed that subtyping alcoholism might be an efficient strategy for mapping susceptibility genes. Cluster analysis is one of the possible statistical techniques for such a purpose. We required that, ideally, the variables to be used in cluster analysis should be: 1) related to alcoholism, 2) related to the severity of alcoholism, and 3) familial, i.e., correlated within families. Only three variables met all three conditions. Those included age of onset of ALDX1, smoking, and TPQ-HA. A global score of symptoms of alcoholism was systematically introduced as one of the variables composing a subset for cluster analysis, although this score did not show any familial aggregation. Our strategy led to a strong evidence of linkage at D15S230 in only 20 families whose members are mainly characterized by heavy smoking.