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Serotonergic signaling abnormalities have been implicated in suicide. Tryptophan hydroxylase TPH, the rate limiting enzyme of serotonin biosynthesis and the serotonin transporter SLC6A4, involved in the reuptake of serotonin from the synaptic gap, play major role in serotonergic signaling. In this study, we aimed to compare the levels of expression of these serotoninrelated genes between suicide completers and controls and to identify genetic loci involved in their regulation. SLC6A4, TPH1, and TPH2mRNA levels were measured in the ventral prefrontal cortex VPFC of 39 suicide completers and 40 matched controls. To identify the molecular basis of gene expression variation, we performed association studies between cisacting polymorphisms and SLC6A4, TPH1, and TPH2transcript levels. Finally, association analyses were carried out between suicide and TPH2cissingle nucleotide polymorphisms SNPs in cohorts of 154 suicide completers and 289 control subjects. Whereas SLC6A4and TPH1mRNA expression levels did not differ between suicides and controls, TPH2levels were found significantly increased P  0.003 in suicide completers. We observed that SNP rs10748185 located in the promoter region of TPH2significantly affect levels of TPH2mRNA expression. However, we did not find positive association between this eQTL rs10748185 and suicide. Here, we report the simultaneous analysis of the expression of three serotoninrelated genes in the VPFC of suicide victims and controls. This study showed that TPH2expression levels were increased in the VPFC of suicide victims. Although, we identified a genetic variant that explains variance in TPH2expression, we did not find evidence associating this cisregulatory SNP with suicidal behavior. © 2010 WileyLiss, Inc.

It has recently been proposed that the SSAT gene plays a role in the predisposition to suicidal behavior. SSATexpression was found to be downregulated in the brain of suicide completers. In addition, a single nucleotide polymorphism SNP rs6526342 was associated both with variation in SSATexpression and with suicidal behavior. In this study, we aimed to characterize the relationship between SSAT dysregulation and suicide behavior. To this end, we measured SSAT expression levels in the ventral prefrontal cortex VPFC of suicide completers n  20 and controls n  20 and found them to be significantly downregulated in suicide victims P  0.007. To identify the basis of the regulation of SSAT expression, we performed an association analysis of 309 SNPs with SSAT transcript levels in 53 lymphoblastoid cell lines from the CEPH collection. We then examined the methylation status of the SSAT promoter region in males and females suicide completers and control subjects whose SSAT brain expression had been measured. We found no evidence to support a role for SNPs in controlling the level of SSAT expression. SSAT promoter methylation levels were not different between suicide completers and controls and did not correlate with SSAT expression levels. In addition, we found no indication of a genetic association between suicidal behavior and SNPs located within the SSAT gene. Our study provides new results which show that dysregulation of SSAT expression does play a role in suicide behavior. However, our data do not support any association between rs6526342 and variation in SSAT expression or suicidal behavior. © 2008 WileyLiss, Inc.

Suicide is one of the ten most common causes of death in Western countries. It involves genetic vulnerability factors and is often associated with major depression. A Japanese team reported an association between the insertion allele of the angiotensinconverting enzyme ACE gene insertiondeletion ID polymorphism with completed suicide. The ACEID polymorphism was investigated in two independent casecontrol studies, one involving 64 suicide completers and 90 controls who all underwent forensic investigations, the second one consisting of 588 suicide attempters and 639 controls. In the two population samples studied a statistically significant risk of suicidal behavior was observed for subjects bearing the DD genotype. These results suggest a possible role of the reninangiotensin system in suicidal behavior. © 2008 WileyLiss, Inc.

Anger‐related personality traits are considered contributory risk factors for suicidal behavior. According to twin studies, they are partially under genetic control and their various clinical expressions have been associated with serotonergic and catecholaminergic activities. A functional polymorphism on the human catechol‐O‐methyltransferase (COMT) gene, which codes for the catecholamines inactivating enzyme COMT, has been shown to influence aggressive and anger‐related traits in various clinical populations. The aim of the present study was to investigate the association between anger traits (as characterized by the State‐Trait Anger Expression Inventory, STAXI) and COMT Val158Met polymorphism in suicide attempters (n = 427) and control subjects (n = 185). Results showed that the high activity genotype (Val/Val) was more frequent in suicide attempters than in normal controls. Moreover, the Val/Val genotype markedly affected the scores on two STAXI subscales—Trait Anger and Anger Control—in female suicide attempters, thus suggesting a possible gender effect of the COMT genotype on a stable personality trait. These results are discussed in the light of recently published data on the effect of COMT Val158Met polymorphism on different cognitive and behavioral traits. © 2007 Wiley‐Liss, Inc.

Genetic factors have been associated with the vulnerability to suicidal behavior. We previously reported decision‐making impairment in suicide attempters and hypothesized that these cognitive alterations may represent an endophenotype of suicidal behavior. In this study, we aimed to investigate the influence of four serotonin‐related genes relevant to suicidal behavior on decision‐making, in a large population of suicide attempters. The Iowa Gambling Task was used to assess decision‐making in 168 patients with a personal history of attempted suicide. Patients were genotyped for four serotonergic polymorphisms: 5HTTLPR, TPH1 A218C, MAOA u‐VNTR, and TPH2 rs1118997. Patients carrying the 5HTTLPR‐ll and ‐sl, TPH1‐CC and ‐AC, MAOA‐HH (in women) and TPH2‐AA genotypes significantly improved their performance during the task, suggesting a genetic modulation of the learning process required for advantageous decision‐making. In contrast, genotypes previously associated with a higher risk of suicidal behavior, a greater sensitivity to the environment and a higher propensity to negative feelings are those conferring poorer learning abilities. We hypothesize that the influence of genetic factors on the vulnerability to suicidal behavior may partly be achieved through their modulation of decision‐making and particularly its learning component. © 2007 Wiley‐Liss, Inc.

The authors assessed whether collection by mail of saliva and buccal cells for genetic analysis was feasible in participants recruited through the Internet. In 2003, 14,773 visitors of a smoking cessation website were invited by e-mail to take part in the study. Salivettes (plastic vials containing a cotton roll) were mailed to participants, for collection of saliva and buccal cells. Because of limited resources, the authors stopped recruitment when 392 participants (3% of 14,733) were registered. They received 315 saliva samples back (80% of 392). Salivary cotinine was analyzed in 145 daily smokers. Cotinine concentration could be assessed in 141 samples (97%) (range 0.7–899 ng/ml, median 260 ng/ml). DNA extraction was achieved in all the 285 samples in which it was attempted. Quality of DNA was assessed by optical density measurements and by polymerase chain reaction amplification of a gene coding for the α-4 nicotinic receptor, with the detection of a known polymorphism. Successful results were obtained in 235 samples (82% of 285). Thus collecting saliva by mail for cotinine and DNA analysis in participants recruited through the internet produced samples of good quality at a reasonable cost. This approach should be valuable for genetic epidemiology and pharmacogenetic research.

Compelling evidence suggests that serotonin system dysfunction is associated with certain behavioral disorders, including suicidal behavior and impulsive aggression. A functional polymorphism in the promoter region of the monoamine oxidase A gene (uVNTR) was recently identified and the presence of the 2–3 alleles was found to be associated with a higher level of transcription, central nervous system serotonergic responsivity and impulsive aggression. A dinucleotide repeat in intron 2 of the gene (monoamine oxidase A-CAn) has been described previously, and is in linkage disequilibrium with the variable number of tandom repeats (VNTR). The aim of the study was to investigate, in a large sample, whether the monoamine oxidase A gene was involved in the susceptibility to suicidal behavior.

The basis of suicidal behavior (SB) is complex and multifactorial. Numerous risk factors have been identified. Epidemiological genetics studies (family studies, twin studies, adoption studies) suggest that there is a genetic basis to SB and that this genetic basis is specific and independent from the genetic factors implicated in predisposition to psychiatric disorders associated with SB (bipolar disorder, schizophrenia, alcoholism). Recently, new molecular genetics tools have been designed to identify the genetic factors that predispose certain individuals to disorders of complex etiology. Biological psychiatry studies have suggested that the physiopathology of SB involves dysfunctioning of the serotonin system. The first genetic association studies tested candidate genes encoding proteins involved in serotonin metabolism. The results of these studies suggest that the gene coding for the limiting enzyme in the synthesis of serotonin, tryptophan hydroxylase (TPH), and the gene encoding the serotonin transporter are involved in predisposition to SB. Furthermore, it is likely that these genes interact with each other and with environmental factors (early) and that they have different phenotypic consequences. One of the main aims of studies currently underway is to identify the precise phenotypes associated with genes that predispose to SB or intermediate phenotypes (impulsivity, inability to control anger, etc.). © 2005 Wiley‐Liss, Inc.

Bipolar affective disorder (BPAD) is a complex psychiatric disorder with a major genetic contribution. Abnormalities in serotonergic function have been implicated in its aetiology. The 5HT2A receptor (5HT2AR) gene is a strong candidate gene for involvement in BPAD, but previous association studies have reported conflicting results. These data are difficult to interpret because most negative results were obtained with small samples. The aim of this study was to test the association between the 5HT2AR gene and BPAD in a large West European sample. We studied the −1438G/A and the His452Tyr polymorphisms, for haplotype analysis to increase both informativity and the likelihood of detecting an association between BPAD and the 5HT2AR gene. We analysed the genotype, allele and haplotype distributions of two 5HT2AR gene variants in a population of 356 BPAD patients, which we compared with 208 healthy controls. We also carried out exploratory analysis in clinical subgroups of patients defined according to personal history of mood disorders, suicidal behaviour, comorbid psychiatric disorders and family history of affective disorders. We found no difference between BPAD patients and controls for allele, genotype and haplotype distributions. Exploratory analysis in subgroups of BPAD patients showed only a marginal difference in haplotype distribution between controls and BPAD patients with antidepressant‐induced mania (P = 0.018). This difference was not significant after correction for multiple testing. Our study suggests that the 5HT2AR gene is unlikely to be involved in genetic susceptibility to BPAD but should be further investigated in a pharmacogenetic study. © 2004 Wiley‐Liss, Inc.

Gratacos et al. [2001: Cell 106:367‐379] described an interstitial duplication dup(15)q24q26 (DUP25) in patients with anxiety disorders; this duplication was found in approximately 90% of patients and in 7% of controls. In order to determine if DUP25 is present in additional individuals susceptible to panic attacks, we tested 44 patients with anxiety disorders, using probes 251c23 and 216c14 mapping in the 15q24 and 15q26 region. We have not detected any DUP25. Our results suggest that DUP25 is not common in people with anxiety disorders in the population tested here. © 2004 Wiley‐Liss, Inc.

Genes encoding proteins involved in serotonergic metabolism are major candidates in association studies of suicidal behavior. The tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, is a major candidate gene and has been extensively studied in association studies of suicidal behavior, providing conflicting results. It is difficult to interpret these conflicting results due to lack of power, ethnic heterogeneity, and variations in the sampling strategies (in particular for controls) and in the polymorphism of the TPH gene studied. Meta-analyses can improve the statistical power for the analysis of the effects of candidate vulnerability factors. The analysis of the sources of heterogeneity that contribute to these conflicting results is an important step in the interpretation of these conflicting association results and in the interpretation of the results of a meta-analysis. We selected all of the published association studies between the TPH gene polymorphism and suicidal behavior. Nine association studies between the A218C TPH polymorphism and suicidal behavior fulfilled the inclusion criteria. A significant association was observed between the A218C polymorphism and suicidal behavior using the fixed effect method (odds ratio (OR) = 1.62; 95% confidence interval (CI) = [1.26; 2.07]) and the random effect method (OR = 1.61; 95% CI = [1.11; 2.35]). The analysis of the sources of heterogeneity showed that two studies (one positive and one negative) significantly deviated from the calculated global effect. The meta-analysis performed after removing those two studies also revealed a significant association between the TPH A218C polymorphism and suicidal behavior. Both analyses suggested that the A allele has a dose-dependent effect on the risk of suicidal behavior. © 2004 Wiley-Liss, Inc.

A joint analysis of five paternal half-sib Holstein families that were part of two different granddaughter designs (ADR- or Inra-design) was carried out for five milk production traits and somatic cell score in order to conduct a QTL confirmation study and to increase the experimental power. Data were exchanged in a coded and standardised form. The combined data set (JOINT-design) consisted of on average 231 sires per grandsire. Genetic maps were calculated for 133 markers distributed over nine chromosomes. QTL analyses were performed separately for each design and each trait. The results revealed QTL for milk production on chromosome 14, for milk yield on chromosome 5, and for fat content on chromosome 19 in both the ADR- and the Inra-design (confirmed within this study). Some QTL could only be mapped in either the ADR- or in the Inra-design (not confirmed within this study). Additional QTL previously undetected in the single designs were mapped in the JOINT-design for fat yield (chromosome 19 and 26), protein yield (chromosome 26), protein content (chromosome 5), and somatic cell score (chromosome 2 and 19) with genomewide significance. This study demonstrated the potential benefits of a combined analysis of data from different granddaughter designs.

There is compelling evidence that suicidal behavior is associated with the dysfunction of the serotonin system. A functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was recently identified and the presence of the short allele was associated with lower gene expression, lower 5-HT uptake and violent suicidal behavior. Thus, we attempted to determine whether 5-HTTLPR is also involved in the susceptibility to non-violent suicidal behavior. We compared the genotype from 166 West European Caucasians who attempted suicide by a non-violent mean with 139 controls with no history of suicidal behavior from the same ethnic origin. The frequencies of the S allele and the SS genotype in the sample who attempted non-violent suicide were not statistically different to those in the controls. Thus, the genetically altered expression of the 5-HT transporter might be associated with more severe or violent suicidal behavior, but not with non-violent suicidal behavior. © 2002 Wiley-Liss, Inc.

BACKGROUND: To determine whether the tryptophan hydroxylase gene (ie, the gene that codes for the rate-limiting enzyme in the metabolic pathway of serotonin) may be a susceptibility factor for suicidal behavior. METHODS: Genotypic and allelic frequencies at a polymorphic Ava II restriction site were revealed with the use of the complementary DNA tryptophan hydroxylase probe C2-38 in 62 suicide attempters. The psychiatric characteristics of these suicide attempters were determined using the Schedule for Affective Disorders and Schizophrenia—Lifetime version with modification for the study of anxiety disorders, and these characteristics were compared with those in 52 healthy controls. RESULTS: No association between tryptophan hydroxylase and suicidal behavior was detected. CONCLUSION: The tryptophan hydroxylase gene was not a susceptibility factor for suicidal behaviors in the group of suicide attempters in this study.

Mediterranean myoclonus is a progressive myoclonus epilepsy with autosomal recessive inheritance. Anothe form has been described in Finland, the so‐called Baltic myoclonus. Mediterranean myoclonus and Baltic myoclonus are also known as Unverricht‐Lundborg disease. Linkage analyses have shown that the genes for both these forms of myoclonus are closely linked to 21q22.3 DNA markers, suggesting that they are caused by mutations at the same locus (EPM1). Recently, two heterozygous mutations were found in the cystatin B gene in patients with Unverricht‐Lundborg disease. We report recombinational and linkage disequilibrium mapping of EPM1, and cystatin B gene sequencing, in 14 consanguineous pedigrees with Mediterranean myoclonus. Linkage to 21q22.3 DNA markers was observed in all these families. Haplotype analysis suggests that a common mutation segregates within these pedigrees, and that this mutation is different from the common one responsible for the Finnish form of Unverricht‐Lundborg disease. No mutation was found in the exons or splice junctions of the cystatin B gene in the 14 pedigrees.

QUANTITATIVE trait loci (QTL) approach was used in CXB recombinant inbred mice for preliminary identification of candidate regions on the mouse genome that influence sleep. The only provisional QTLs identified were associated with paradoxical sleep (PS). PS during the light period was associated with markers on chromosome 7 between 7 and 20 centimorgan from the centromere. For PS during the dark period, a single QTL was identified on chromosome 5, near the Clockgene. The 24 h amount of PS was influenced by markers on chromosomes 2, 17, and 19. This first QTL mapping study strongly suggests that a complex behaviour like PS can be controlled by only a few genes.

Benign familial neonatal convulsions (BFNC) is an idiopathic form of epilepsy beginning within the first six months of life. Its genetic origin and autosomal dominant mode of inheritance have been suspected since its first description. Recently, the BFNC gene has been localised within chromosome 20q in one large pedigree. For the first time, we confirm here (with D20S19 and D20S20) the close linkage of BFNC to chromosome 20q in six French predigrees. In addition, the existence in these families of several cases of febrile convulsions (FC), another epileptic syndrome with an autosomal dominant genetic component, led us to study the possibility of a genetic background identical to BFNC. Our results suggest the existence of different susceptibility genes for BFNC and FC.

Several studies have implicated the tyrosine hydroxylase (TH) locus within the 11p15 region in susceptibility to manic depressive illness (MDI). This possibility was further investigated by both parametric (lod score) and nonparametric (affected-pedigree-member and a case-control study) methods of analysis in 11 French MDI families and in a sample of 200 unrelated subjects. Both types of analyses corroborate the implication of this locus, and positive lod scores were obtained in two families, which most likely reflects genetic heterogeneity. Statistical analyses were also performed including available data from published reports. These analyses, which allowed for genetic heterogeneity, substantiated our findings. The combined maximum lod score for all the families studied was 3.68 at θ = 0.00 (number of families: 36) assuming heterogeneity (α=15%,P=0.01). Taken together these results converge to suggest that the risk factors for MDI lie in the 11p15 region with TH being the most likely candidate gene.

The telomeric copy (t) of the survival motor neuron (SMN) gene is homozygously deleted in more than 90% of patients with infantile motor neuron disease (MND). In the general population, no homozygous SMNt deletion has been found, whereas 5% of centromeric SMN (SMNc) deletions can be observed. Although SMNtdeletions appear causal for infantile and at least some adult‐onset spinal muscular atrophy (SMA) (type IV), the respective role of SMNdeletions remains unclear in adult‐onset MNDs. We studied SMN gene in three different groups of patients with adult‐onset MNDs. In sporadic amyotrophic lateral sclerosis (ALS; n = 177) ands familial ALS (n = 66), no SMNtdeletion had been found, and the frequency of SMNcdeletions was not increased. Converesly, among the 14 patients with sporadic pure lower MND (LMND), we found 2 patients with homozygous SMNtdeletions (14%) and 5 patients with homozygous SMNc deletions (36%). These data suggest that (1) SMNt deletions do not account for the major part, if any, of adult‐onset LMND cases; and (2) SMNcdeletions act as a susceptibility factor for LMNDs in adults. The clinical and gentic heterogeneity of LMND cases, including SMA type IV, are yet to be unexplained. Further studies on large groups of adult‐onset LMND patients are warranted to refine its nosology.

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A joint analysis of five paternal half-sib Holstein families that were part of two different granddaughter designs (ADR- or Inra-design) was carried out for five milk production traits and somatic cell score in order to conduct a QTL confirmation study and to increase the experimental power. Data were exchanged in a coded and standardised form. The combined data set (JOINT-design) consisted of on average 231 sires per grandsire. Genetic maps were calculated for 133 markers distributed over nine chromosomes. QTL analyses were performed separately for each design and each trait. The results revealed QTL for milk production on chromosome 14, for milk yield on chromosome 5, and for fat content on chromosome 19 in both the ADR- and the Inra-design (confirmed within this study). Some QTL could only be mapped in either the ADR- or in the Inra-design (not confirmed within this study). Additional QTL previously undetected in the single designs were mapped in the JOINT-design for fat yield (chromosome 19 and 26), protein yield (chromosome 26), protein content (chromosome 5), and somatic cell score (chromosome 2 and 19) with genomewide significance. This study demonstrated the potential benefits of a combined analysis of data from different granddaughter designs.

We analyzed the distribution of FMR1, FXR1, FXR2 mRNA, and FMRP in whole normal human embryos and in the brains of normal and fragile X fetuses. The distributions of mRNA for the 3 genes in normal whole embryos and in the brains of normal male and female carrier fetuses were similar, with large amounts of mRNA in the nervous system and in several non-nervous system tissues. No FMR1 (mRNA and protein) was detected and no evident neuropathologic abnormalities found in the brains of male carrier fetuses, suggesting that the FMR1 product (FMRP) may have no crucial function in early stages of nervous system development. FXR1 and FXR2 mRNA had the same distribution and similar intensity in the brains of normal and pathologic fetuses (female and male carriers). The coexpression in the same tissues of FMR1, FXR1, and FXR2, associated with the normal expression of FXR1 and FXR2 and the absence of obvious neuropathological abnormalities in pathological brains, supports the notion that the FXR1 and FXR2 proteins partially compensate for FMRP function. However, the absence of significant overexpression of FXRI and FXR2 in pathological brains suggests that these genes do not compensate for the lack of FMR1 expression. Alternatively, FMR1, FXR1, and FXR2 proteins may not have compensatory functions, but instead may regulate functions by hetero or homo oligomerization, as suggested by other studies. Thus, a dominant negative effect of abnormal multimeric protein complexes lacking FMRP (e.g. by modification of FXR1 and FXR2 protein functions) may result in the fragile X syndrome phenotype.