Timothy J. Crow

Microduplications of 16p11.2 are associated with schizophrenia.

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 × 10−5, OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 × 10−7), bipolar disorder (P = 0.017) and autism (P = 1.9 × 10−7). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 × 10−13). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

A genome-wide search for schizophrenia susceptibility genes

We completed a systematic genome-wide search for evidence of loci linked to schizophrenia using a collection of 70 pedigrees containing multiple affected individuals according to three phenotype classifications: schizophrenia only (48 pedigrees; 70 sib-pairs); schizophrenia plus schizoaffective disorder (70 pedigrees; 101 sib-pairs); and a broad category consisting of schizophrenia, schizoaffective disorder, paranoid or schizotypal personality disorder, psychosis not otherwise specified (NOS), delusional disorder, and brief reactive psychosis (70 pedigrees; 111 sib-pairs). All 70 families contained at least one individual affected with chronic schizophrenia according to DSM-III-R criteria. Three hundred and thirty-eight markers spanning the genome were typed in all pedigrees for an average resolution of 10.5 cM (range, 0-31 cM) and an average heterozygosity of 74.3% per marker. The data were analyzed using multipoint nonparametric allele-sharing and traditional two-point lod score analyses using dominant and recessive, affecteds-only models. Twelve chromosomes (1, 2, 4, 5, 8, 10, 11, 12, 13, 14, 16, and 22) had at least one region with a nominal P value <0.05, and two of these chromosomes had a nominal P value <0.01 (chromosomes 13 and 16), using allele-sharing tests in GENEHUNTER. Five chromosomes (1, 2, 4, 11, and 13) had at least one marker with a lod score >2.0, allowing for heterogeneity. These regions will be saturated with additional markers and investigated in a new, larger set of families to test for replication.

Broca's area : Nomenclature, anatomy, typology and asymmetry

In this review, we (i) describe the nomenclature of Brocas area and show how the circumscribed definition of Brocas area is disassociated from Brocas aphasia, (ii) describe in detail how the gross anatomy of Brocas area varies between people, and how the definitions vary between studies, (iii) attempt to reconcile the findings of structural asymmetry of Brocas area with the differences in methodological approaches, (iv) consider the functional significance of cytoarchitectonic definitions of Brocas area, and (v) critically elucidate the significance of circumscribed regions of cortex for language lateralisation and language development. Contrary to what has previously been reported in the literature, asymmetry of Brocas area has not been reproducibly demonstrated, particularly on a gross morphological level. This may be due to major inconsistencies in methodology (including different anatomical boundaries, measurement techniques and samples studied) or that the sulcal contours defining Brocas area are so naturally variable between people making a standard definition difficult. Cytoarchitectonic analyses more often than not report leftward asymmetry of some component of area 44 and/or area 45. If a structural asymmetry of Brocas area does exist, it is variable, which differs from that of the functional asymmetry of language, which is more consistent. One reason for this might be that the link between cellular architecture, connectivity and language function still remains to be elucidated. There is currently no convincing explanation to associate asymmetry of Brocas area with the lateralisation of language.

Schizophrenia as a transcallosal misconnection syndrome

Schizophrenic symptoms are conceived as arising from inter-individual variability in the distribution of those fibres that connect asymmetrical regions of the hemispheres related to language. Language (a bihemispheric phenomenon) arose as a result of a genetic change that allowed the two hemispheres to develop with a degree of independence. One component, the phonological output sequence, became localised to the dominant hemisphere, interacting through the corpus callosum with other component functions, including the associated meanings, in the non-dominant hemisphere. Nuclear symptoms are a consequence of failure of segregation of these two functions. This failure is associated with abnormal connectivity between the hemispheres and relates particularly to those regions that are late developing and differ between the sexes.

Cerebral lateralization is delayed in children who later develop schizophrenia

The origins of schizophrenia are obscure. One suggestion is that it represents a component of the genetic variation associated with the establishment of dominance in one or other cerebral hemisphere, a mechanism that has been crucial in the evolution of language. Indices of cerebral hemispheric dominance (hand, foot and eye preference, speed of checking squares) recorded on the 16,980 children in the UK National Child Development Study cohort were examined in relation to psychiatric admission by the age of 28 years. Diagnoses were established by the application of Present State Examination criteria to case notes. Pre-schizophrenic children (n = 34-36) were more likely (p < 0.0003) to be rated by their mothers as ambidextrous at the age of 7 years, and at 11 years were less (p < 0.01) strongly right-handed than their peers in the cohort population on a test of relative hand skill: children who later developed affective psychosis (n = 25) or neurosis (n = 60) did not differ significantly from controls. Delay in establishing dominance in one hemisphere could be the critical factor that predisposes to schizophrenia.

A continuum of psychosis, one human gene, and not much else - the case for homogeneity

The contention of this paper is that psychoses are not a collection of separate and unrelated diseases, but a set of diverse expressions of a single underlying entity. It will be argued that there is a basic homogeneity of pathogenesis, that there are not multiple predisposing genes but a single gene that is associated with significant diversity. Therefore the problem is a unitary one. The challenge is to identify the nature and function of the gene. It will be argued that the gene is that by which homo sapiens has separated from other primate species, and that the diversity arises from selective pressures which continue to act on this specifically human gene.

Evidence for linkage to psychosis and cerebral asymmetry (relative hand skill) on the X chromosome.

The hypothesis that psychosis arises as a part of the genetic diversity associated with the evolution of language generates the prediction that illness will be linked to a gene determining cerebral asymmetry, which, from the evidence of sex chromosome aneuploidies, is present in homologous form on the X and Y chromosomes. We investigated evidence of linkage to markers on the X chromosome in 1) 178 families multiply affected with schizophrenia or schizoaffective disorder with a series of 16 markers spanning the centromere (study 1), and 2) 180 pairs of left-handed brothers with 14 markers spanning the whole chromosome (study 2). In study 1, excess allele-sharing was observed in brother-brother pairs (but not brother-sister or a small sample of sister-sister pairs) over a region of approximately 20 cM, with a maximum LOD score of 1.5 at DXS991. In study 2, an association between allele-sharing and degree of left-handedness was observed extending over approximately 60 cM, with a maximum lod score of 2.8 at DXS990 (approximately 20 cM from DXS991). Within the overlap of allele-sharing is located a block in Xq21 that transposed to the Y chromosome in recent hominid evolution and is now represented as two segments on Yp. In one of two XX males with psychosis we found that the breakpoint on the Y is located within the distal region of homology to the block in Xq21. These findings are consistent with the hypothesis that an X-Y homologous determinant of cerebral asymmetry carries the variation that contributes to the predisposition to psychotic illness.

Automatic analysis of cerebral asymmetry: an exploratory study of the relationship between brain torque and planum temporale asymmetry.

Leftward occipital and rightward frontal lobe asymmetry (brain torque) and leftward planum temporale asymmetry have been consistently reported in postmortem and in vivo neuroimaging studies of the human brain. Here automatic image analysis techniques are applied to quantify global and local asymmetries, and investigate the relationship between brain torque and planum temporale asymmetries on T1-weighted magnetic resonance (MR) images of 30 right-handed young healthy subjects (15 male, 15 female). Previously described automatic cerebral hemisphere extraction and 3D interhemispheric reflection-based methods for studying brain asymmetry are applied with a new technique, LowD (Low Dimension), which enables automatic quantification of brain torque. LowD integrates extracted left and right cerebral hemispheres in columns orthogonal to the midsagittal plane (2D column maps), and subsequently integrates slices along the brains anterior-posterior axis (1D slice profiles). A torque index defined as the magnitude of occipital and frontal lobe asymmetry is computed allowing exploratory investigation of relationships between this global asymmetry and local asymmetries found in the planum temporale. LowD detected significant torque in the 30 subjects with occipital and frontal components found to be highly correlated (P<0.02). Significant leftward planum temporale asymmetry was detected (P<0.05), and the torque index correlated with planum temporale asymmetry (P<0.001). However, torque and total brain volume were not correlated. Therefore, although components of cerebral asymmetry may be related, their magnitude is not influenced by total hemisphere volume. LowD provides increased sensitivity for detection and quantification of brain torque on an individual subject basis, and future studies will apply these techniques to investigate the relationship between cerebral asymmetry and functional laterality.

Auditory cortex asymmetry, altered minicolumn spacing and absence of ageing effects in schizophrenia

The superior temporal gyrus, which contains the auditory cortex, including the planum temporale, is the most consistently altered neocortical structure in schizophrenia (Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia. Schizophr Res 2001; 49: 1-52). Auditory hallucinations are associated with abnormalities in this region and activation in Heschls gyrus. Our review of 34 MRI and 5 post-mortem studies of planum temporale reveals that half of those measuring region size reported a change in schizophrenia, usually consistent with a reduction in the left hemisphere and a relative increase in the right hemisphere. Furthermore, female subjects are under-represented in the literature and insight from sex differences may be lost. Here we present evidence from post-mortem brain (N = 21 patients, compared with 17 previously reported controls) that normal age-associated changes in planum temporale are not found in schizophrenia. These age-associated differences are reported in an adult population (age range 29-90 years) and were not found in the primary auditory cortex of Heschls gyrus, indicating that they are selective to the more plastic regions of association cortex involved in cognition. Areas and volumes of Heschls gyrus and planum temporale and the separation of the minicolumns that are held to be the structural units of the cerebral cortex were assessed in patients. Minicolumn distribution in planum temporale and Heschls gyrus was assessed on Nissl-stained sections by semi-automated microscope image analysis. The cortical surface area of planum temporale in the left hemisphere (usually asymmetrically larger) was positively correlated with its constituent minicolumn spacing in patients and controls. Surface area asymmetry of planum temporale was reduced in patients with schizophrenia by a reduction in the left hemisphere (F = 7.7, df 1,32, P < 0.01). The relationship between cortical asymmetry and the connecting, interhemispheric callosal white matter was also investigated; minicolumn asymmetry of both Heschls gyrus and planum temporale was correlated with axon number in the wrong subregions of the corpus callosum in patients. The spacing of minicolumns was altered in a sex-dependent manner due to the absence of age-related minicolumn thinning in schizophrenia. This is interpreted as a failure of adult neuroplasticity that maintains neuropil space. The arrested capacity to absorb anomalous events and cognitive demands may confer vulnerability to schizophrenic symptoms when adult neuroplastic demands are not met.

Accelerated evolution of Protocadherin11X/Y: A candidate gene-pair for cerebral asymmetry and language†‡

It has been argued that cerebral asymmetry (the “torque”) is the characteristic that defines the human brain and that morphological findings in psychosis are consistent with a deviation in this sex‐dependent dimension of brain growth. Evidence from sex chromosome aneuploidies and an association within families between sex and handedness is consistent with the presence of a determinant of cerebral asymmetry (a possible correlate of language) on the X and the Y chromosomes. During hominid evolution a 3.5 Mb translocation occurred from the ancestral X chromosome to the Y chromosome, resulting in duplication of the Protocadherin11X gene, such that it is represented on the X and Y chromosomes in man, whereas there is a single X‐linked gene in other mammals. We re‐date the duplicative translocation to 6 million years ago, that is, close to the chimpanzee–hominid bifurcation. Sequence comparisons with the chimpanzee, bonobo, gorilla, and orangutan indicate that in contrast to earlier purifying selection there has been accelerated change in the Protocadherin11X ectodomain as well as the Protocadherin11Y sequence in the hominid lineage since the duplication. The evolutionary sequence of events together with the prior case for an X‐Y homologous gene suggests that this gene‐pair is a candidate for the evolution of hominid‐specific characteristics including the sexual dimorphism of cerebral asymmetry, a putative correlate of language.