Kamran Razi

Sex-dependent effects of schizophrenia: an MRI study of gyral folding, and cortical and white matter volume

Alterations, sometimes sex-dependent, in volumes and gyral structure of areas of cerebral cortex have been reported in schizophrenia. Such changes imply an anomaly of connectivity. The gyrification, percentage of tissue volume attributed to white matter, cortical volume and white matter volume were measured from magnetic resonance images in males and females with (n = 61) and without (n = 42) schizophrenia. The frontal, temporal and an amalgam of occipital and parietal lobes were examined in both hemispheres. There was no effect of schizophrenia on the gyrification of the brain. For the volume of occipito-parietal white matter, females with schizophrenia had bilaterally lower volumes, while males with schizophrenia had greater volumes than controls. It is concluded that the changes in connectivity underlying the pathogenesis of schizophrenia are sex-specific and expressed in occipito-parietal white matter.

Hand preference and hand skill in families with schizophrenia.

Direction and degree of handedness in humans are variable between individuals and thought to be in part inherited. Several studies have shown an increase in non-right handedness among patients with schizophrenia, and some have included unaffected relatives. The present study was designed to determine whether reduced right handedness is more frequent among individuals with schizophrenia as compared with their well relatives and whether it clusters within families having multiple ill members. A total of 259 families comprising 418 individuals diagnosed with schizophrenia or schizoaffective disorder, 54 individuals with other psychoses, 145 family members with depression and other minor diagnoses, and 288 unaffected individuals were included. Hand preference was assessed by the Annett Scale and right relative to left hand skill measured using the Tapley-Bryden test. For all assessments of hand preference and hand skill, females were significantly more lateralised towards the right than males. Those individuals with schizophrenia or schizoaffective disorder had significantly less right hand preference than their unaffected relatives when measured as a quantitative index of items from the Annett Scale (p = .019), but not categorically (right, left or mixed). In contrast, there was no difference in hand skill between diagnostic groups. Hand preference was significantly correlated among male-male affected sibling pairs (p = .01) and similar results were found for hand skill among the total group of affected pairs (p = .001). Although these results only partially support a relationship between handedness and schizophrenia, they nevertheless draw attention to sex differences in hand preference and the familial aspects of hand preference in this disorder. More direct approaches to the genetics of cerebral dominance and psychosis are required.

Failure to establish linkage on the X chromosome in 301 families with schizophrenia or schizoaffective disorder

The hypothesis that a gene for susceptibility to psychosis (specifically in the X-Y homologous class) is located on the sex chromosomes has been proposed. Such a gene would account for the excess of sex chromosome anomalous males and females in populations of patients with psychosis, a tendency towards concordance by sex within families, and sex differences associated with psychosis and its underlying brain pathology. In earlier studies we observed small positive LOD scores in Xp11, and in a more recent and larger cohort of 178 sibling pairs, a peak multipoint nonparametric LOD score of 1. 55 at the locus DXS8032 in Xq21. The present study with a new set of markers extended the cohort to 301 ill sibling pairs and their parents. Despite the increase in sample size, the LOD score did not increase. A peak NPL of 1.55 was observed at the locus DXS1068 in proximal Xp, a region remote from the previous report. Separating families into those who were more likely to have X chromosome inheritance (maternal with no male to male transmission) did not yield stronger findings. In spite of the evidence that psychosis is related to a sex-dependent dimension of cerebral asymmetry, it is concluded that no consistent linkage of schizophrenia to the X chromosome can be demonstrated. In the context of the general failure of replication of linkage in psychosis, the possibility that the genetic predisposition to psychosis is contributed to by epigenetic modification rather than variations in the nucleotide sequence has to be considered.

No evidence for a parent-of-origin effect detected in the pattern of inheritance of schizophrenia

BACKGROUND Schizophrenia is a complex genetic disorder with no clear pattern of inheritance. Epigenetic modification of genes may thus play a role in its transmission. METHODS In our study, 439 families with at least two ill siblings with schizophrenia (208 with unilineal transmission) were examined for evidence of a parent-of-origin effect (e.g., evidence of parental imprinting on the familial transmission of schizophrenia). RESULTS No significant difference in the prevalence of maternal compared with paternal transmission was found. In addition, affected male subjects did not differ from affected female subjects in the proportion of their offspring diagnosed with schizophrenia. CONCLUSIONS Although the transmission of schizophrenia may be influenced by epigenetic events, our study fails to find evidence that one epigenetic mechanism, a parent-of-origin imprinting effect, determines whether an individual expresses the illness.

Investigation of a candidate gene for schizophrenia on Xq13 previously associated with mental retardation and hypothyroidism

Weak support for linkage of schizophrenia to proximal Xq has previously been reported. In addition, an increased prevalence of thyroid disorder has been noted in families of individuals with schizophrenia. Recently, a gene mapped to Xq13 termed HOPA has been found to be associated with mental retardation, hypothyroidism, and depression and to function as a coactivator for the thyroid receptor. We therefore examined the HOPA gene in a group of 111 probands from a larger cohort of multiplex families with schizophrenia, several of whom (n = 53) also had a family history of hypothyroidism. Four males and two females were found with an alteration in exon 42 of the HOPA gene compared with 8/492 males and 18/471 females (942 X chromosomes) compared with consecutively screened newborns (chi(2) = 3.92, P < 0.05). However, when available family members of each of the probands with an exon 42 variation were subsequently screened, the mutation did not segregate with schizophrenia in three of five families, although all 6 probands with an exon 42 variation did have hypothyroidism in either themselves (n = 3) or their mothers (n = 3) (P < 0.008). These findings replicate prior findings demonstrating an association between HOPA polymorphisms and hypothyroidism. In addition, the increased frequency of HOPA variants in this population may also provide a genetic basis for the familial association of thyroid disease and schizophrenia.

Clinical characteristics of schizophrenia in multiply affected Spanish origin families from Costa Rica.

Sixty-six families from Costa Rica with multiply ill sets of siblings were examined in detailed clinical evaluations and compared with 59 similarly evaluated families from the USA. Eighty-six unrelated Costa Rican individuals with a schizophrenia spectrum diagnosis and no other ill siblings were an additional comparison group. This study was undertaken to examine whether schizophrenia in Costa Rica has similar clinical and demographic characteristics to that in the USA, whether a homogeneous population such as that in Costa Rica might harbor a specific definable subtype, and whether singletons have similar or differing characteristics from individuals in multiplex families. Overall, schizophrenia in Costa Rica is similar to that in any other geographic location. The same symptoms, sex ratio and age of onset characteristics predominate. However, there was significantly less prevalence of affective symptoms (depression and mania) and drug abuse among the Costa Rican multiplex families by comparison with those from the USA. The families with only one ill member from Costa Rica had significantly more alcohol abuse than the multiply affected families. Within multiplex families (both USA and Costa Rica), age of onset was found to have a familial component. Family sibship size was significantly greater in Costa Rica than the USA for the generation with illness studied. However, these siblings had overall fewer children. In Costa Rica, the male but not the female siblings with schizophrenia had reduced fecundity compared with their well siblings. These families from Costa Rica will be used in further molecular genetic studies to determine whether the illness etiology can be traced to one or more specific genetic linkages.

Lack of evidence for linkage to chromosomes 13 and 8 for schizophrenia and schizoaffective disorder

A previous report [Blouin et al., 1998: Nat Genet 20:70-73] suggesting linkage to chromosomes 13q32 and 8p21 in families with schizophrenia led us to investigate these regions in a large set of 301 multiplex families with schizophrenia. Multipoint analyses failed to reveal evidence for linkage to any portion of chromosome 13, while only a weakly positive score was present on 8p using the identical marker reported in the earlier report. Failure to confirm the Blouin et al claims in a substantially larger cohort adds emphasis to the inconsistency of the findings concerning linkage in schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:235-239, 2000.

The Third Annual Pharmacogenetics in Psychiatry Meeting, 2004.

The first session (Chair: David Collier, Institute of Psychiatry, King’s College London, London, UK) focused on antidepressant drug response. David Goldman (NIAAA, Rockville, Maryland, USA) presented new data on the oft-studied serotonin transporter polymorphism 5-HTTLPR, indicating that his group had detected a sequence variant within the long allele of 5-HTTLPR that has significant effects on transcription. The detection of this new variant yields long (l) alleles with similar effects as short (s) alleles on gene transcription, and thus may explain some of the divergent findings associated with this variant. The new sequence variant is not rare (up to 15% frequency) and will need to be considered in analyses of 5-HTTLPR in psychiatric pharmacogenetic studies of antidepressant drug response. An assay has been developed in Dr Goldman’s laboratory at the NIAAA. Eric J. Peters (UCSF, San Francisco, California, USA) presented data on the association of seven serotonin pathway genes (HTR1A, HTR2A and HTR2C, TPH1, TPH2, SLC6A4 and MAOA) to fluoxetine response in unipolar major depression. His group had resequenced 95 patients with unipolar major depressive disorder and detected 115 polymorphisms, of which 71 were new. Continued evidence is found of his initial reported findings of the association between HTR2A, TPH1 and TPH2, and fluoxetine response. Alessandro Serretti (University Vita-Salute – School of Medicine, Milan, Italy) initially presented data on a cohort of 185 patients followed after their recovery from a major depressive episode. Of note, a CLOCK gene polymorphism (T3111C) that appears to influence messenger RNA stability was significantly associated with relapse within 6 months after recovery. Finally, Greer M. Murphy, Jr (Stanford University, Stanford, California, USA) presented data on a multicenter, double-blind study of 246 cognitively intact, geriatric depressed patients enrolled in a clinical trial of mirtazapine versus paroxetine. His group has analyzed a number of candidate genes including 5-HTTLPR, 5-HT2A, 5-HT2C and APOE, and observed significant associations between specific alleles and antidepressant response to treatment, and associations to dropout from treatment due to drug-induced adverse events.