Context There are many published twin studies of schizophrenia. Although these studies have been reviewed previously, to our knowledge, no review has provided quantitative summary estimates of the impact of genes and environment on liability to schizophrenia that also accounted for the different ascertainment strategies used. Objective To calculate meta-analytic estimates of heritability in liability and shared and individual-specific environmental effects from the pooled twin data. Data Sources We used a structured literature search to identify all published twin studies of schizophrenia, including MEDLINE, dissertation, and books-in-print searches. Study Selection Of the 14 identified studies, 12 met the minimal inclusion criteria of systematic ascertainment. Data Synthesis By using a multigroup twin model, we found evidence for substantial additive genetic effects—the point estimate of heritability in liability to schizophrenia was 81% (95% confidence interval, 73%-90%). Notably, there was consistent evidence across these studies for common or shared environmental influences on liability to schizophrenia—joint estimate, 11% (95% confidence interval, 3%-19%). Conclusions Despite evidence of heterogeneity across studies, these meta-analytic results from 12 published twin studies of schizophrenia are consistent with a view of schizophrenia as a complex trait that results from genetic and environmental etiological influences. These results are broadly informative in that they provide no information about the specific identity of these etiological influences, but they do provide a component of a unifying empirical basis supporting the rationality of searches for underlying genetic and common environmental etiological factors.

/pdf/schizophrenia-as-a-complex-trait-evidence-from-a-meta-37rwvji6gi.pdf

Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies.

The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.

/pdf/neuregulin-1-and-susceptibility-to-schizophrenia-4bw1d6giiv.pdf

Neuregulin 1 and Susceptibility to Schizophrenia

We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10−7). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.

https://www.hal.inserm.fr/inserm-00634944/document

Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4

Background: Twin studies of bipolar affective disorder (BPD) have either been small or have not used explicit diagnostic criteria. There has been little use of genetic model fitting and no analyses to explore the etiological overlap with unipolar depression (UPD). Methods: Sixty-seven twin pairs, 30 monozygotic and 37 dizygotic, in which the proband had BPD were ascertained, and lifetime diagnoses were made using DSM-IV criteria. Univariate models were applied to estimate the contribution of additive genetic and environmental effects. Bipolar data were then combined with those from 68monozygoticand109dizygoticpairsinwhichtheproband had UPD. Two models were explored: a classic 2-threshold approach, in which BPD and UPD occupy thesamecontinuumofliabilitybutdifferinseverity,and a correlated liability model of mania and depression. Results:Heritability of BPD was estimated at 85% (95% confidence interval [CI], 0.73-0.93) using narrow concordance and 89% (95% CI, 0.61-1.0) using broad concordance, with no shared environmental effects detected. A 2-threshold model was an unsatisfactory fit. Fitting a correlated liability model revealed a genetic correlation of 0.65 (95% CI, 0.58-0.75) between mania and depression and a correlation of 0.59 (95% CI, 0.150.84) for nonfamilial environment. Approximately 71% of the genetic variance for mania was not shared with depression.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/207452/yoa20662.pdf

The Heritability of Bipolar Affective Disorder and the Genetic Relationship to Unipolar Depression

There is abundant evidence, some of it reviewed in this paper, that personality traits are substantially influenced by the genes. Much remains to be understood about how and why this is the case. We argue that placing the behavior genetics of personality in the context of epidemiology, evolutionary psychology, and neighboring psychological domains such as interests and attitudes should help lead to new insights. We suggest that important methodological advances, such as measuring traits from multiple viewpoints, using large samples, and analyzing data by modern multivariate techniques, have already led to major changes in our view of such perennial puzzles as the role of "unshared environment" in personality. In the long run, but not yet, approaches via molecular genetics and brain physiology may also make decisive contributions to understanding the heritability of personality traits. We conclude that the behavior genetics of personality is alive and flourishing but that there remains ample scope for new growth and that much social science research is seriously compromised if it does not incorporate genetic variation in its explanatory models.

Genes, evolution, and personality.

Background Previous twin studies have supported a genetic contribution to the major categories of psychotic disorders, but few of these have employed operational diagnostic criteria, and no such study has been based on a sample that included the full range of functional psychotic disorders. Methods A total of 224 twin probands (106 monozygotic, 118 dizygotic) with a same-sex co-twin and a lifetime history of psychosis was ascertained from the service-based Maudsley Twin Register in London, England. Research Diagnostic Criteria psychotic diagnoses were made on a lifetime-ever basis. Main-lifetime diagnoses of DSM-III-R and International Statistical Classification of Diseases, 10th Revision schizophrenia were also made. Probandwise concordance rates and correlations in liability were calculated, and biometrical model fitting applied. Results A substantial genetic contribution to variance in liability was confirmed for the major diagnostic categories except Research Diagnostic Criteria depressive psychosis and unspecified functional psychosis, where familial transmission was confirmed, but the relative contribution of genetic and common environmental factors was unclear. Heritability estimates for Research Diagnostic Criteria schizophrenia, schizoaffective disorder, mania, DSM-III-R schizophrenia, and International Statistical Classification of Diseases, 10th Revision schizophrenia were all between 82% and 85%. None of the estimates differed significantly from any other. Conclusions Heritability estimates for schizophrenia, schizoaffective disorder, and mania were substantial and similar. Population morbid risk estimates were inferred rather than directly measured, but the results were very similar to those from studies where morbid risks were directly estimated.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/204765/yoa8188.pdf

Heritability Estimates for Psychotic Disorders: The Maudsley Twin Psychosis Series

Background.—Aminergic neurotransmitter activity has been studied in many neuropsychiatric diseases by means of a self-administered questionnaire proposed by Cloninger. Given that central aminergic modulation plays a major role in the pathophysiology of primary headaches, we investigated the personality dimensions related to aminergic neurotransmitter activity in patients with migraine and tension-type headache.

Methods.—From a consecutive series of 230 patients, we selected those presenting with migraine and tension-type headache according to the International Headache Society criteria. All patients were assessed by means of the Cloninger 100-item self-report Tridimensional Personality Questionnaire and a depression scale. The four dimensions of personality are novelty seeking (dopaminergic), harm avoidance (serotonergic), reward dependence (noradrenergic), and persistence (glutaminergic).

Results.—One hundred twenty-one patients presenting with migraine and 42 with tension-type headache were recruited. The results indicate significantly higher harm avoidance scores (P<.001) in both patients with migraine and those with tension-type headache than in controls. Furthermore, patients with migraine had a significantly low score in the novelty seeking dimension (P<.001). When we compared only the two groups of patients with headache, we found that the persistence dimension alone was significantly higher in patients with migraine than in those with tension-type headache (P<.05). No differences were observed either in the overall scores of the other personality dimensions or in the depression scale scores.

Conclusions.—The Tridimensional Personality Questionnaire results support a role of the serotonergic system in both migraine and tension-type headache pathophysiology. A dysfunction of dopaminergic and glutaminergic tone seems to be a specific feature of migraine.

Aminergic Tone Correlates of Migraine and Tension‐type Headache: A Study Using the Tridimensional Personality Questionnaire

Background: Previous twin studies have supported a genetic contribution to the major categories of psychotic disorders, but few of these have employed operational diagnostic criteria, and no such study has been based on a sample that included the full range of functional psychotic disorders. Methods: A total of 224 twin probands (106 monozygotic, 118 dizygotic) with a same-sex co-twin and a lifetime history of psychosis was ascertained from the servicebased Maudsley Twin Register in London, England. Research Diagnostic Criteria psychotic diagnoses were made on a lifetime-ever basis. Main-lifetime diagnoses of DSM-III-R and International Statistical Classification of Diseases, 10th Revision schizophrenia were also made. Probandwise concordance rates and correlations in liability were calculated, and biometrical model fitting applied. Results: A substantial genetic contribution to variance in liability was confirmed for the major diagnostic categories except Research Diagnostic Criteria depressive psychosis and unspecified functional psychosis, where familial transmission was confirmed, but the relative contribution of genetic and common environmental factors was unclear. Heritability estimates for Research Diagnostic Criteria schizophrenia, schizoaffective disorder, mania, DSM-III-R schizophrenia, and International Statistical Classification of Diseases, 10th Revision schizophrenia were all between 82% and 85%. None of the estimates differed significantly from any other. Conclusions: Heritability estimates for schizophrenia, schizoaffective disorder, and mania were substantial and similar. Population morbid risk estimates were inferred rather than directly measured, but the results were very similar to those from studies where morbid risks were directly estimated. Arch Gen Psychiatry. 1999;56:162-168

Heritability Estimates for Psychotic Disorders

Low nerve growth factor (NGF) plasma levels in schizophrenic patients: a pilot study

To assess the relationship between hemispheric differences in information processing and interhemispheric asymmetries in terms of brain bioelectrical activity, we correlated scores on the MMPI Depression scale with interhemispheric asymmetry, measured as peak amplitude and latency of the P3 component of somatosensory evoked potentials (SEPs) at the frontocortical region of 14 healthy unselected volunteers (8 men and 6 women) who were about to start a course in autogenic training. The sample was subdivided into two groups on the basis of the median score on the MMPI Depression scale. Subjects scoring above the median showed a right lateralization at the frontocentral region and a significantly shorter P3 latency at the right hemisphere compared to the left.

P. Venturi

Papers

Heritability Estimates for Psychotic Disorders: The Maudsley Twin Psychosis Series

Aminergic Tone Correlates of Migraine and Tension‐type Headache: A Study Using the Tridimensional Personality Questionnaire

Heritability Estimates for Psychotic Disorders

Low nerve growth factor (NGF) plasma levels in schizophrenic patients: a pilot study

Frontal hemisphere lateralization and depressive personality traits