Psychiatric genetics: search for phenotypes

Leboyer, M.; Leboyer, Marion; Bellivier, Frank; Jouvent, Roland; Nosten‐Bertrand, Marika; Mallet, Jacques; Pauls, David L.

doi:10.1016/s0166-2236(97)01187-9

Cited by 296 publications

(183 citation statements)

References 47 publications

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“…By studying the core symptoms of an illness, a candidate symptom approach is a promising step towards improved characterization of subgroups of disorders and eventually to the identification of specific vulnerability markers. 1 A good example of such an approach is the study of anhedonia. Anhedonia is defined as a reduced capacity to experience pleasure in normally pleasurable situations and is a key symptom of major depression (MDD) and schizophrenia (SZ).…”

Section: Introductionmentioning

confidence: 99%

“…9,10 Endophenotypes are subclinical traits that are associated with the expression of an illness and represent the genetic liability of the disorder in non-affected individuals. 1 The neural system underlying reward and pleasure is well defined in humans. In previous neuroimaging studies, monetary reward, 11,12 pleasurable responses to music 13 and the viewing of pleasant pictures [13][14][15][16] have all been associated with activity within the nucleus accumbens, the ventral caudate and the ventral putamen.…”

Section: Introductionmentioning

confidence: 99%

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Individual differences in trait anhedonia: a structural and functional magnetic resonance imaging study in non-clinical subjects

et al. 2007

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Anhedonia, the reduced capacity to gain pleasure from pleasurable experiences, is a key symptom of major depression and schizophrenia. Reduced hedonic capacity can also be measured as an enduring trait in non-clinical subjects. Such altered hedonic capacity is likely the result of a basic neuropsychophysiological dysfunction and a vulnerability marker that potentially precedes and contributes to the liability of developing psychiatric disorders. The characterization of the structural and functional neural correlates of trait anhedonia in nonclinical individuals may provide new insights for the early detection of such psychiatric diseases. Twenty-nine non-clinical subjects were scanned at the Montreal Neurological Institute. Trait anhedonia was measured using the Chapman Revised Physical Anhedonia Scale. Semi-automated and automated structural MRI segmentation techniques were used to explore structural correlates of trait anhedonia. Seventeen of the 29 subjects also underwent a functional imaging task where responses to the viewing of affective stimuli were examined to identify the functional correlates of trait anhedonia. Trait anhedonia was inversely related to anterior caudate volume, but positively related to ventromedial prefrontal cortex activity during the processing of positive information. These findings may reflect a specific kind of vulnerability for the development of psychiatric affective disorders and suggest that trait anhedonia may be linked to a volumetric reduction in the basal ganglia and to a prefrontal functional abnormality during hedonic processing.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Individual differences in trait anhedonia: a structural and functional magnetic resonance imaging study in non-clinical subjects

et al. 2007

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“…To disentangle the genetic and clinical heterogeneity of the disorder, a clinical approach based on candidate symptoms has been proposed. 3 Age at onset (AAO; that is age at the first mood episode) is one of the most relevant indicators to identify homogeneous subgroups that may reduce the underlying genetic heterogeneity. Three AAO subgroups have been identified for BD [4][5][6] and there is strong evidence showing that genetic factors make a greater contribution to the disease in the early-onset subgroup than in the other subgroups.…”

Section: Introductionmentioning

confidence: 99%

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

et al. 2009

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Bipolar disorder (BD) is one of the most common and persistent psychiatric disorders. Earlyonset BD has been shown to be the most severe and familial form. We recently carried out a whole-genome linkage analysis on sibpairs affected by early-onset BD and showed that the 20p12 region was more frequently shared in our families than expected by chance. The synaptosomal-associated protein SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release, and for which abnormal protein levels have been reported in postmortem studies of bipolar patients. We hypothesised that variations in the gene encoding SNAP25, located on chromosome 20p12, might influence the susceptibility to early-onset BD. We screened SNAP25 for mutations and performed a case-control association study in 197 patients with early-onset BD, 202 patients with late-onset BD and 136 unaffected subjects. In addition, we analysed the expression level of the two SNAP25 isoforms in 60 brains. We showed that one variant, located in the promoter region, was associated with early-onset BD but not with the late-onset subgroup. In addition, individuals homozygous for this variant showed a significant higher SNAP25b expression level in prefrontal cortex. These results show that variations in SNAP25, associated with an increased gene expression level in prefrontal cortex, might predispose to early-onset BD. Further analyses of this gene, as well as analysis of genes encoding for the SNAP25 protein partners, are required to understand the impact of such molecular mechanisms in BD.

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“…Anomalies in behavioral, neuroanatomical, and neurophysiological asymmetry have been widely documented in schizophrenic patients, supporting lateralization as a good candidate symptom that could contribute to clarifying schizophrenia heterogeneity (Leboyer et al, 1998). A metaanalysis of 19 studies on schizophrenia showed that the prevalence of non-right-handedness was significantly higher in patients than in healthy subjects (Sommer et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Constitutive Hyperdopaminergia is Functionally Associated with Reduced Behavioral Lateralization

Morice

Denis

Macario

et al. 2004

Neuropsychopharmacol

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According to the dopamine (DA) hypothesis of schizophrenia and the strong evidence for decreased cerebral lateralization in schizophrenic patients, we postulated that hyperactivity of the dopaminergic system could be associated with a reduced behavioral lateralization in mice. Mice lacking the dopamine transporter (DAT) gene were used as a genetic model of persistent hyperdopaminergia. The DAT null mutation was transferred on C57BL/6JOrl (B6) and DBA/2JOrl (D2) inbred backgrounds for more than 10 generations of backcrossing to derive three DAT strains, B6, D2, and B6 Â D2(F 1 ). Adult mutant mice of the three DAT strains and their littermates were tested for paw preference using Collins' protocol. Our results demonstrated that, whatever the genetic background, persistent hyperdopaminergia directly impairs the degree of lateralization without affecting the direction. Our results support the degree of lateralization as a good candidate phenotype to further improve genetic analysis of cerebral lateralization in normal and pathological conditions. Neuropsychopharmacology Keywords: schizophrenia; direction and degree of asymmetry; paw preference; knockout mice; cocaine INTRODUCTIONAnomalies in behavioral, neuroanatomical, and neurophysiological asymmetry have been widely documented in schizophrenic patients, supporting lateralization as a good candidate symptom that could contribute to clarifying schizophrenia heterogeneity (Leboyer et al, 1998). A metaanalysis of 19 studies on schizophrenia showed that the prevalence of non-right-handedness was significantly higher in patients than in healthy subjects (Sommer et al, 2001). Similarly, in the meta-analysis of three prospective followup studies, pre-schizophrenic subjects were significantly more often non-right-handed than the general population (Sommer et al, 2001). Furthermore, in vivo imaging studies of schizophrenia have provided evidence that the right-left asymmetry of the dopamine (DA) synthesis capacity and of the dopamine transporter (DAT) binding in the caudate are both lost in antipsychotic-naive patients (Hietala et al, 1999(Hietala et al, , 1995Hsiao et al, 2003;Laakso et al, 2000). In addition, neuroleptics are able to change the balance of hemispheric activity, thus improving left-hemispheric attentional processes (for a review, see Gruzelier, 1999), and a recent study demonstrated that haloperidol-induced downregulation of DA synthesis was significantly greater in the left than in the right striatum (Grunder et al, 2003). Finally, a highly significant correlation was reported between depressive symptoms in antipsychotic-naive schizophrenia and DA synthesis capacity in the left striatum (Hietala et al, 1999).Taken together, these data support the hypothesis of a potential link between cerebral lateralization and schizophrenia, and suggest that abnormal asymmetry of the dopaminergic transmission could be one of the key neurobiological substrates for this functional relationship. Based on the DA hypothesis of schizophrenia, which attributes the positive sc...

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Psychiatric genetics: search for phenotypes

Cited by 296 publications

References 47 publications

Individual differences in trait anhedonia: a structural and functional magnetic resonance imaging study in non-clinical subjects

Individual differences in trait anhedonia: a structural and functional magnetic resonance imaging study in non-clinical subjects

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

Constitutive Hyperdopaminergia is Functionally Associated with Reduced Behavioral Lateralization

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