Genome-wide linkage scan of bipolar disorder in a Colombian population isolate replicates Loci on chromosomes 7p21-22, 1p31, 16p12 and 21q21-22 and identifies a novel locus on chromosome 12q.

BACKGROUND/AIMS: Bipolar disorder (BP) is a severe psychiatric illness, characterised by alternating episodes of depression and mania, which ranks among the top ten causes of morbidity and life-long disability world-wide. We have previously performed a whole-genome linkage scan on 6 pedigrees segregating severe BP from the well-characterised population isolate of Antioquia, Colombia. We recently collected genotypes for the same set of 382 autosomal microsatellite markers in 9 additional Antioquian BP pedigrees. Here, we report the analysis of the combined pedigree set. METHODS: Linkage analysis using both parametric and nonparametric approaches was conducted for 3 different diagnostic models: severe BP only (BPI); mood disorders (BPI, BPII and major depression); and psychosis (operationally defined by the occurrence of at least 1 episode of hallucinations and/or delusions). RESULTS AND CONCLUSION: For BPI only, the most interesting result was obtained for chromosome 7p21.1-p22.2 under a recessive model of inheritance (heterogeneity LOD score = 2.80), a region that had previously been linked to BP in a study on Portuguese Island families. For both BPI and mood disorders, nonparametric analyses identified a locus on chromosome 12ct-q14 (nonparametric linkage = 2.55 and 2.35, respectively). This locus has not previously been reported as a candidate region for BP. Additional candidate regions were found on chromosomes 1p22-31 (mood disorders) and 21q21-22 (BPI), 2 loci that have repeatedly been implicated in BP susceptibility. Linkage analysis of psychosis as a phenotype identified candidate regions on chromosomes 2q24-31 and 16p12-q12. The finding on chromosome 16p is noteworthy because the same locus has been implicated by genome-wide association analyses of BP.

Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the widespread development of distinctive tumors termed hamartomas. TSC-determining loci have been mapped to chromosomes 9q34 (TSC1) and 16p13 (TSC2). The TSC1 gene was identified from a 900-kilobase region containing at least 30 genes. The 8.6-kilobase TSC1 transcript is widely expressed and encodes a protein of 130 kilodaltons (hamartin) that has homology to a putative yeast protein of unknown function. Thirty-two distinct mutations were identified in TSC1, 30 of which were truncating, and a single mutation (2105delAAAG) was seen in six apparently unrelated patients. In one of these six, a somatic mutation in the wild-type allele was found in a TSC-associated renal carcinoma, which suggests that hamartin acts as a tumor suppressor.

Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene.

All affected patients in four families with autosomal dominant familial renal tubular acidosis (dRTA) were heterozygous for mutations in their red cell HCO3-/Cl- exchanger, band 3 (AE1, SLC4A1) genes, and these mutations were not found in any of the nine normal family members studied. The mutation Arg589--> His was present in two families, while Arg589--> Cys and Ser613--> Phe changes were found in the other families. Linkage studies confirmed the co-segregation of the disease with a genetic marker close to AE1. The affected individuals with the Arg589 mutations had reduced red cell sulfate transport and altered glycosylation of the red cell band 3 N-glycan chain. The red cells of individuals with the Ser613--> Phe mutation had markedly increased red cell sulfate transport but almost normal red cell iodide transport. The erythroid and kidney isoforms of the mutant band 3 proteins were expressed in Xenopus oocytes and all showed significant chloride transport activity. We conclude that dominantly inherited dRTA is associated with mutations in band 3; but both the disease and its autosomal dominant inheritance are not related simply to the anion transport activity of the mutant proteins.

The planning of rural health research: rurality and rural population issues.

Rurality and rural population issues require special consideration when planning both qualitative and quantitative health research in rural areas. The objective of this article was to explore the issues that require attention when planning the research. This is the first of two articles and focus on issues that require consideration when undertaking rural health research. The diversity of study populations, the feasibility of a research topic, the selection of a research team, and the cultural traditions of Indigenous communities, are all aspects of rural health research planning that require attention. Procedures such as identifying the characteristics of the population, the selection of measures of rurality appropriate for the research topic, the use of local liaison persons, decisions on the use of 'insider' or 'outsider' researchers, and the identification of skills resources available, increase the quality of the research outcomes. These issues are relevant to both qualitative and quantitative research. Procedures are available to address issues of particular concern in developing appropriate methods for rural health research. While we have concentrated on Australian issues and solutions, rural localities in other countries may face similar issues. Attention to rurality and rural situations when planning rural health research, results in studies that support the continued improvement of health in rural communities.

The conducting and reporting of rural health research: rurality and rural population issues.

Rurality and rural population issues require consideration when conducting and reporting on rural health research. A first article focused on the planning stage of the research. The objective of this article is to explore conducting and reporting issues that require attention when undertaking rural health research. The privacy of participants, the collection of data, the cultural traditions of Indigenous communities, the dissemination of results, and giving something back to the community, are all aspects of conducting and reporting rural health research that require attention. Procedures such as identifying the characteristics of the population, attention to safety issues when collecting data, the use of local liaison persons and acknowledging the ownership of intellectual property, increase the quality of the research outcomes. They are issues that are relevant to both qualitative and quantitative research methods. Procedures are available to address issues of particular concern in developing appropriate methods for rural health research. While we have concentrated on Australian issues, and possible solutions, rural localities in many other countries may face similar issues. In any rural setting, paying attention to issues that may affect the conducting and reporting of rural health research will hopefully result in studies that support the continued improvement of health in rural communities.

C4 complement allotypes in juvenile dermatomyositis.

Twenty probands with juvenile dermatomyositis and their relatives were studied to determine the inherited segregation patterns of class I, II, and III HLA region markers including C4A, C4B, Bf, and C2 complement polymorphisms. The extended haplotype B8, DR3, C4A*Q0, C4B*1, C2*C, and Bf*S was present in 13 of the 20 probands. Three other probands also carried a haplotype with a null allele for C4A and two further probands carried a null allele for C4B; only two probands had no detectable C4 null allele. These data confirm previous studies showing high frequencies of B8 and DR3 in patients with juvenile dermatomyositis, but show that there is a higher association with null alleles of C4. This suggests that the C4 genes are either themselves the disease-susceptibility genes or are in very strong linkage disequilibrium with such genes.

HLA class III haplotypes in multicase rheumatoid arthritis families.

The class III complement proteins (C2, BF, C4A, and C4B) were studied in 57 multicase rheumatoid arthritis (RA) families. When the gene frequencies for RA probands were compared to a normal control panel (162 haplotypes), a significantly higher frequency of the rare variant C4B*3 was observed (p less than 0.05). No significant differences were seen for the other C2, BF, C4A, or C4B alleles. The most common haplotype found in the probands was HLA-Cw5,B44,C2*C,BF*S,C4A*3,C4B*3,DR4, occurring with a frequency of 0.088. Haplotypes containing HLA-DR4 and Bw62 were found to carry either C4A*3,C4B*3; C4A*3,C4B*1; or C4A*4,C4B*2. When only haplotypes containing DR4 were compared between probands and controls, the frequency of the C4B*3-bearing haplotype remained higher in the probands. It is concluded that Bw62,C4A*3,C4B*3DR4 is a haplotype which is especially associated with RA. The low frequency in the RA population of this haplotype indicates that C4B*3 has a minor role in overall RA susceptibility.

Genetic heterogeneity in tuberous sclerosis. Study of a large collaborative dataset.

Tuberous sclerosis (TSC) is a multisystem autosomal dominant hamartosis whose genetics is complicated by reduced penetrance and widely varying clinical expression. Results of linkage analyses have variously suggested two different locations for a TSC gene. A collaborative dataset has been assembled to clarify the issue of genetic heterogeneity. We have now analyzed the data from a combined sample of 111 families. Using Ott's HOMOG programs, we completed three tests of homogeneity: (1) for chromosome 9q, (2) for chromosome 11q, and (3) for the combined 9q and 11q data. For test 1 the chi-square (1 df) was 21.54 (p less than 0.001), for test 2 the chi-square (1 df) was 0.13 (p greater than 0.35), and for test 3 the chi-square (2 df) was 37.61 (p less than 0.0001). Additionally, we examined the combined data for evidence that a third, as yet unlinked locus exists. Results of this last test were suggestive but not significant. Clearly loci for TSC are present on both chromosomes 9q and 11q. The maximum likelihood estimate of the proportion of chromosome 9q-linked families is 0.38, for chromosome 11q-linked families is 0.47, and for the unlinked type 0.15. Alternative explanations for these latter families include chance sampling of recombinants, nongenetic phenocopies, or misclassification.

Lead in umbilical blood, indoor air, tap water, and gasoline in Boston.

A strong statistical correlation was found among the monthly averages of lead concentrations in umbilical cord blood (about 500 births/month), indoor air (12 sites/month), and gasoline lead sales between March, 1980 and April, 1981 in Boston. Tap water lead (24/month) variations did not correlate with blood lead in this population.

A mutation screen of the TSC1 gene reveals 26 protein truncating mutations and 1 splice site mutation in a panel of 79 tuberous sclerosis patients.

The entire coding region of the TSC1 gene has been screened for mutations in 79 unrelated patients with tuberous sclerosis. Causative mutations have been found in 27 of these patients and five other variations in the gene have been identified. 26 of the mutations are predicted to cause premature truncation of the protein product of the gene and one mutation is in a splice site. The mutation screen has revealed that TSC1 mutations are rarer in sporadic tuberous sclerosis patients than in familial cases. We have also found that the only previously described case of non-penetrance can no longer be described as such, and that a single ungual fibroma is not necessarily diagnostic of tuberous sclerosis, important findings for the genetic counselling of tuberous sclerosis patients.

Two loci for tuberous sclerosis: one on 9q34 and one on 16p13.

32 families informative for the segregation of Tuberous sclerosis (TSC) have been examined for genetic markers on chromosomes 9, 11, 12 and 16. In one large family there was clear evidence of linkage to markers on chromosome 16p13.3 (lodscore with D16S291 of 4.7 at theta = 0) but other families were too small to give individually convincing lodscores. Combined results for all families gave positive results with ABO/DBH on chromosome 9 (max lod 2.63) and with D16S291 on chromosome 16 (max lod 3.98) at values of theta of 0.2 in each case. Further analysis showed strong evidence for heterogeneity with approximately half the families linked to a locus TSC1 on chromosome 9 between ASS and D9S298 and half to TSC2 on chromosome 16 close to D16S291. There was no definite support for a third locus although in many families this could not be excluded. In three families the segregation pattern of TSC remains unexplained. In two of these the family apparently segregates for TSC1 but in each case a single affected individual appeared to exclude the whole of the candidate region. Preliminary analysis of clinical features did not reveal any definite differences in incidence of mental handicap between individuals in different linkage groups or with different sex of the parent of origin. The frequencies of periungual fibromas and facial angiofibromas were also similar in both linkage groups. The difficulties of detecting linkage in small families where there is locus heterogeneity are discussed. The program ZZ was found to be helpful in this respect.

The -1021C->T DBH gene variant is not associated with epilepsy or antiepileptic drug response.

Dopamine beta-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine (NE). Animal studies show that genes in the NE pathway are candidates for susceptibility to epilepsy and antiepileptic drug (AED) response. The authors genotyped the -1021C-->T major functional polymorphism in the DBH gene in 675 patients with epilepsy and 1,087 controls. The authors found no association with epilepsy, several epilepsy subtypes, or AED response. The results suggest that the -1021C-->T variant does not contribute to epilepsy.

Non-penetrance in tuberous sclerosis.

As a result of extreme clinical variability in tuberous sclerosis, with one well-documented example of non-penetrance, phenotypically normal siblings or children of patients with tuberous sclerosis are thought to be at increased risk of having children with the disease. We report that the case of apparent non-penetrance that was previously described is the result of two independent tuberous-sclerosis mutations in the same family.

Mapping ESTs to the TSC1 candidate interval by use of the 'Science 96' transcript map.

The transcription map of the human genome published by Schuler et al. (1996) is a valuable resource in which approximately one quarter of all human genes have been mapped with respect to genetic framework markers using radiation hybrids. We have taken information from this map to provide potential genes within the TSC1 candidate region on chromosome 9q34. In so doing we have been able to provide an independent assay of the quality of the radiation hybrid mapping by using somatic cell hybrids and a 2 Mb cosmid contig covering the TSC1 region as mapping tools. In addition, we have built sequence contigs of ESTs for 25 clusters. This has shown that about 20% of the relevant EST clusters in the Unigene resource (Boguski & Schuler 1995) contain chimaeric clones.

Mapping studies on human mitochondrial glutamate oxaloacetate transaminase.

Data from six primary hybrids and twenty-two subclones have confirmed the assignment of the mitochondrial form of glutamate oxaloacetate transaminase to chromosome 16. Family studies have provided independent confirmation of this and have suggested the gene order PGP-16qh-GOT2-HP. These studies were made easier by the development of a new stain for the detection of GOT activity.