Donna M. Brown

Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat.

Hypertension, diabetes and hyperlipidemia are risk factors for life-threatening complications such as end-stage renal disease, coronary artery disease and stroke. Why some patients develop complications is unclear, but only susceptibility genes may be involved. To test this notion, we studied crosses involving the fawn-hooded rat, an animal model of hypertension that develops chronic renal failure. Here, we report the localization of two genes, Rf-1 and Rf-2, responsible for about half of the genetic variation in key indices of renal impairment. In addition, we localize a gene, Bpfh-1, responsible for about 26% of the genetic variation in blood pressure. Rf-1 strongly affects the risk of renal impairment, but has no significant effect on blood pressure. Our results show that susceptibility to a complication of hypertension is under at least partially independent genetic control from susceptibility to hypertension itself.

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.

An integrated genetic linkage map of the laboratory rat

Abstract. The laboratory rat, Rattus novegicus, is a major model system for physiological and pathophysiological studies, and since 1966 more than 422,000 publications describe biological studies on the rat (NCBI/Medline). The rat is becoming an increasingly important genetic model for the study of specific diseases, as well as retaining its role as a major preclinical model system for pharmaceutical development. The initial genetic linkage map of the rat contained 432 genetic markers (Jacob et al. 1995) out of 1171 developed due to the relatively low polymorphism rate of the mapping cross used (SHR × BN) when compared to the interspecific crosses in the mouse. While the rat genome project continues to localize additional markers on the linkage map, and as of 11/97 more than 3,200 loci have been mapped. Current map construction is using two different crosses (SHRSP × BN and FHH × ACI) rather than the initial mapping cross. Consequently there is a need to provide integration among the different maps. We set out to develop an integrated map, as well as increase the number of markers on the rat genetic map.The crosses available for this analysis included the original mapping cross SHR × BN reciprocal F2 intercross (448 markers), a GH × BN intercross (205 markers), a SS/Mcw × BN intercross (235 markers), and a FHH/Eur × ACI/Hsd intercross (276 markers), which is also one of the new mapping crosses. Forty-six animals from each cross were genotyped with markers polymorphic for that cross. The maps appear to cover the vast majority of the rat genome. The availability of these additional markers should facilitate more complete whole genome scans in a greater number of strains and provide additional markers in specific genomic regions of interest.

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.