David P. Lennon

Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q

Evidence for suggestive linkage to schizophrenia with chromosome 6q markers was previously reported from a two-stage approach. Using nonparametric affected sib pairs (ASP) methods, nominal p-values of 0.00018 and 0.00095 were obtained in the screening (81 ASPs; 63 independent) and the replication (109 ASPs; 87 independent) data sets, respectively. Here, we report a follow-up study of this 50cM 6q region using 12 microsatellite markers to test for linkage to schizophrenia. We increased the replication sample size by adding an independent sample of 43 multiplex pedigrees (66 ASPs; 54 independent). Pairwise and multipoint nonparametric linkage analyses conducted in this third data set showed evidence consistent with excess sharing in this 6q region, though the statistical level is weaker (p=0.013). When combining both replication data sets (total of 141 independent ASPs), an overall nominal p-value=0.000014 (LOD=3. 82) was obtained. The sibling recurrence risk (lambdas) attributed to this putative 6q susceptibility locus is estimated to be 1.92. The linkage region could not be narrowed down since LOD score values greater than three were observed within a 13cM region. The length of this region was only slightly reduced (12cM) when using the total sample of independent ASPs (204) obtained from all three data sets. This suggests that very large sample sizes may be needed to narrow down this region by ASP linkage methods. Study of the etiological candidate genes in this region is ongoing.

Second Stage of a Genome Scan of Schizophrenia: Study of Five Positive Regions in an Expanded Sample

In a previous genome scan of 43 schizophrenia pedigrees, nonparametric linkage (NPL) scores with empirically derived pointwise P-values less than 0.01 were observed in two regions (chromosomes 2q12-13 and 10q23) and less than 0.05 in three regions (4q22-23, 9q22, and 11q21). Markers with a mean spacing of about 5 cM were typed in these regions in an expanded sample of 71 pedigrees, and NPL analyses carried out. No region produced significant genomewide evidence for linkage. On chromosome 10q, the empirical P-value remained at less than 0.01 for the entire sample (D10S168), evidence in the original 43 pedigrees was slightly increased, and a broad peak of positive results was observed. P-values less than 0.05 were observed on chromosomes 2q (D2S436) and 4q (D4S2623), but not on chromosomes 9q or 11q. It is concluded that this sample is most supportive of linkage on chromosome 10q, with less consistent support on chromosomes 2q and 4q. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:864-869, 2000.

A linkage study of schizophrenia to markers within Xp11 near the MAOB gene

A sex chromosome locus for psychosis has been considered on the basis of some sex differences in genetic risk and expression of illness, and an association with X-chromosome anomalies. Previous molecular genetic studies produced weak evidence for linkage of schizophrenia to the proximal short arm of the X-chromosome, while some other regions were not ruled out. Here we report an attempt to expand the Xp findings in: (i) a multicenter collaboration focusing on 92 families with a maternal pattern of inheritance (Study I), and (ii) an independent sample of 34 families unselected for parental mode of transmission (Study II). In the multicenter study, a parametric analysis resulted in positive lod scores (highest of 1.97 for dominant and 1.19 for recessive inheritance at a theta of 0.20) for locus DXS7, with scores below 0.50 for other markers in this region (MAOB, DXS228, and ARAF1). Significant allele sharing among affected sibling pairs was present at DXS7. In the second study, positive lod scores were observed at MAOB (highest of 2.16 at a theta of 0.05 for dominant and 1.64 at a theta of 0.00 for recessive models) and ALAS2 (the highest of 1.36 at a theta of 0.05 for a recessive model), with significant allele sharing (P = 0.003 and 0.01, respectively) at these two loci. These five markers are mapped within a small region of Xp11. Thus, although substantial regions of the X-chromosome have been investigated without evidence for linkage being found, a locus predisposing to schizophrenia in the proximal short arm of the X-chromosome is not excluded.

Diagnosis of schizophrenia in a matched sample of Australian aborigines

Cross‐cultural phenomenology is one method of studying mental disorders such as schizophrenia. There are few data of this nature available on Australian aborigines. Using a retrospective medical record review of 39 matched pairs of aboriginal and nonaboriginal patients discharged as schizophrenic from a psychiatric hospital, this study investigated whether any phenomenological differences, using DSM‐III‐R criteria, existed between the two groups. Of all criteria, bizarre delusions, social deterioration, illness duration and organic exclusion were statistically significant, with fewer aboriginal subjects having documentation for each of these variables. Possible explanations for these findings, including intergroup phenomenological differences and assessment variation, are discussed.

Puerperal psychosis: Associated clinical features in a psychiatric hospital mother-baby unit

Objective: Current psychiatric diagnostic systems do not regard puerperal psychosis as a separate entity. However, there is continuing debate about the validity and clinical utility of this concept. This paper aims to investigate the prognostic importance of a number of clinical features in a sample of patients with puerperal psychosis. Method: A retrospective case note study was conducted on 42 consecutive admissions to a mother-baby unit in a psychiatric hospital. Data were collected on a range of variables, and diagnoses made according to DSM-III-R and RDC criteria for puerperal psychosis. Results: Maternal hostility toward the baby was the only studied variable to increase the likelihood of the baby being cared for by someone other than the mother, indicating the mothers inability to safely care for the baby. Conclusions: These findings tentatively suggest that it is maternal hostility toward the baby, not puerperal psychosis per se that is associated with foster care.

No support for linkage to the bipolar regions on chromosomes 4p, 18p, or 18q in 43 schizophrenia pedigrees

Following the distinction proposed by Kraepelin[1919], who built on the work of Morel [1860], Hecker[1871] and Kahlbaum [1863], bipolar affective disorder(BPAD) and schizophrenia are generally thought of asseparate disorders. Modern epidemiological studiessupport this view since these disorders generally do notaggregate in the same families [Kendler et al., 1993;Maier et al., 1993]. An alternative view, originally putforward by Griesinger in 1861, is that schizophreniaand affective psychoses may be different expressions ofthe same disorder [Crow, 1986; Griesinger, 1861, asreferenced by Maier et al., 1993]. In support of thisview, cross prevalence studies have demonstrated asignificantly higher rate of unipolar affective illnessamongst the relatives of schizophrenia probands, com-pared with that observed amongst the relatives of con-trol probands [Kendler et al., 1993; Maier et al., 1993;Taylor et al., 1993]. Furthermore, commonality insymptomatology (with both schizophrenic and bipolarpatients experiencing Schneiderian first rank symp-toms), in illness course (deterioration in some severebipolar cases is more typical of the pattern seen inschizophrenia), and in effective treatments (neurolep-tics, lithium) raise the possibility of overlapping caus-ative factors, both genetic and nongenetic.Patients with schizoaffective disorder exhibit bothschizophrenic and affective symptoms in varying pat-terns over time, and in describing this group Kendelland Brockington [1980] raised four possible explana-tions: “that most are really schizophrenic illnesses,that most are really affective illnesses, that they are amixture of schizophrenic and affective illnesses, andthat they constitute a third independent type of psy-chosis” [Kendell and Brockington, 1980, p326]. Geneticstudies have forced the need for pragmatic distinctionsto be made within this group of patients for inclusion/exclusion in either schizophrenia or BPAD linkagestudies. For example, RDC [Endicott and Spitzer,1978] “schizoaffective, mainly schizophrenic” caseshave been included in schizophrenia linkage studies(including the present author’s study), while RDC“schizoaffective, mainly affective” cases have been in-cluded in BPAD linkage studies [Gershon et al., 1988].Taken together, these factors suggest that, whetherclassified as separate disorders or as a continuum,overlap exists between affective and schizophrenic ill-nesses, and that the existence of this clinical and fa-milial overlap raises the possibility of overlapping ae-tiologies, and perhaps shared susceptibility genes.Blackwood and co-workers [Blackwood et al., 1996]reported a peak lod score of 4.1 coincident with D4S394(a40.35) on chromosome 4p16.1 in a cohort of 12 Scot-tish BPAD pedigrees. More recent genome screen re-sults provide additional support for a bipolar predispo-sition gene in this region, particularly withinCaucasian populations [Detera-Wadleigh et al., 1997;Ewald et al., 1998; McInnis, 1997; Nothen, 1997;Philibert et al., 1997]. As with most psychiatric genet-ics findings, there are also negative reports of linkageto bipolar disorder in this region [Raeymaekers, 1997;Rice, 1997; Schofield, 1997].There is one report (an abstract) of a family withcases of schizophrenia and schizoaffective disorder thatgave a positive linkage score (lod 1.96) to markerD4S403, near DRD5, although analysis in an addi-tional 23 pedigrees collected by the same group failedto provide supportive evidence for this finding. [Asher-son et al., 1998].On chromosome 18 there are two distinct regions ofinterest for affective psychoses. Berrettini and co-workers [Berrettini et al., 1994, 1997, 1998] reported asuggestive finding in the analysis of five chromosome18 pericentromeric marker loci (APM,

A genome scan of schizophrenia

OBJECTIVE The goal of this study was to identify chromosomal regions likely to contain schizophrenia susceptibility genes. METHOD A genomewide map of 310 microsatellite DNA markers with average spacing of 11 centimorgans was genotyped in 269 individuals--126 of them with schizophrenia-related psychoses--from 43 pedigrees. Nonparametric linkage analysis was used to assess the pattern of allele sharing at each marker locus relative to the presence of disease. RESULTS Nonparametric linkage scores did not reach a genomewide level of statistical significance for any marker. There were five chromosomal regions in which empirically derived p values reached nominal levels of significance at eight marker locations. There were p values less than 0.01 at chromosomes 2q (with the peak value in this region at D2S410) and 10q (D10S1239), and there were p values less than 0.05 at chromosomes 4q (D4S2623), 9q (D9S257), and 11q (D11S2002). CONCLUSIONS The results do not support the hypothesis that a single gene causes a large increase in the risk of schizophrenia. The sample (like most others being studied for psychiatric disorders) has limited power to detect genes of small effect or those that are determinants of risk in a small proportion of families. All of the most positive results could be due to chance, or some could reflect weak linkage (genes of small effect). Multicenter studies may be useful in the effort to identify chromosomal regions most likely to contain schizophrenia susceptibility genes.