Genetic linkage analysis of bipolar affective disorder in an Old Order Amish pedigree

Summary We have used genetic linkage analysis in an effort to identify a gene responsible for bipolar affective disorder (BAD) in an Old Order Amish pedigree. The initial study of this pedigree showed strong evidence for linkage of the chromosome 11p15 markers HRAS1 and the insulin gene (INS) to BAD, whereas a second report found no evidence for linkage. We have independently determined the INS and HRAS1 genotypes from 81 individuals in this pedigree. A polymerase chain reaction (PCR) assay was used to score INS alleles that are difficult to distinguish from one another by conventional agarose gel electrophoresis. In addition, we used four separate diagnostic models to score individuals with psychiatric illness as either affected or unaffected. No evidence of significant linkage between BAD and the markers was found with either two-point or multipoint analysis regardless of which diagnostic model was used. However, exclusion of the region of chromosome 11 between INS and RAS1 as a possible location for the BAD gene in this family depended on the diagnostic model. Further genetic linkage studies with additional DNA markers that span the genome are necessary to determine the chromosomal location of the BAD gene in this family.     

Linkage to Tourette syndrome is excluded for red-cell acid phosphatase (ACP1) and flanking markers on chromosome 2pter-2p23

A recent linkage study of Tourette syndrome with markers in the distal region of chromosome 2p gave a contradictory result with red-cell acid phosphatase (ACP1) compared to the nearby anonymous DNA markers. A modifier gene that is suspected of leading to reduced penetrance of the gene that causes the degenerative neurologic disorder Joseph disease has been hypothesized to lie on chromosome 2p25 near the ACP1 locus. Because Tourette syndrome (TS) has also been shown to have reduced sex-specific penetrance, ACP1 typings were performed on 12 families segregating TS, and pair-wise linkage analysis was carried out. Linkage was excluded for nearly 15 cM on either side of the ACP1 locus. Unpublished exclusion data from several laboratories permit exclusion of a linkage group extending from 2pter to 2p23. Furthermore, no support for the presence of any type of modifier of TS gene expression could be seen in these data.     

Linkage of tyrosine hydroxylase to four other markers on the short arm of chromosome 11.

Tyrosine hydroxylase is the rate-limiting enzyme in catecholamine synthesis; the gene has previously been cloned and localised to the short arm of chromosome 11. Because of the interest in tyrosine hydroxylase as a candidate gene for manic-depressive psychosis and other affective disorders, we carried out family studies to determine the linkage of tyrosine hydroxylase with insulin, beta-globin, D11S12 and Harvey-ras 1, members of a linkage group which has previously been localised to 11p. Using DNA from the Centre d'Etude du Polymorphisme Humain (CEPH) and from two large British pedigrees, we show that tyrosine hydroxylase is closely linked to these four loci (z = 7.36, theta = 0.04 for linkage to insulin) and suggest a gene order based on multipoint mapping.     

Linkage of familial Hibernian fever to chromosome 12p13.

Autosomal dominant periodic fevers are characterized by intermittent febrile attacks of unknown etiology and by recurrent abdominal pains. The biochemical and molecular bases of all autosomal dominant periodic fevers are unknown, and only familial Hibernian fever (FHF) has been described as a distinct clinical entity. FHF has been reported in three families-the original Irish-Scottish family and two Irish families with similar clinical features. We have undertaken a genomewide search in these families and report significant multipoint LOD scores between the disease and markers on chromosome 12p13. Cumulative multipoint linkage analyses indicate that an FHF gene is likely to be located in an 8-cM interval between D12S77 and D12S356, with a maximum LOD score (Z max) of 3.79. The two-point Z max was 3.11, for D12S77. There was no evidence of genetic heterogeneity in these three families; it is proposed that these markers should be tested in other families, of different background, that have autosomal dominant periodic fever, as a prelude to identification of the FHF-susceptibility gene.     

Linkage disequilibrium of three polymorphic RFLP markers in the apolipoprotein AI-CIII gene cluster on chromosome 11

A panel of glial tumors consisting of 11 low grade gliomas, 9 anaplastic gliomas, and 29 glioblastomas were analyzed for loss of heterozygosity by examining at least one locus for each chromosome. The frequency of allele loss was highest among the glioblastomas, suggesting that genetic alterations accumulate during glial tumor development. The most common genetic alteration detected involved allele losses of chromosome 10 loci; these losses were observed in all glioblastomas and in three of the anaplastic gliomas. In order to delineate which chromosome 10 region or regions were deleted in association with glial tumor development, a deletion mapping analysis was performed, and this revealed the partial loss of chromosome 10 in eight glioblastomas and two of the anaplastic gliomas. Among these cases, three distinct regions of chromosome 10 were indicated as being targeted for deletion: one telomeric region on 10p and both telomeric and centromeric locations on 10q. These data suggest the existence of multiple chromosome 10 tumor suppressor gene loci whose inactivation is involved in the malignant progression of glioma.     

No evidence for significant linkage between bipolar affective disorder and chromosome 18 pericentromeric markers in a large series of multiplex extended pedigrees.

Bipolar affective disorder (BP) is a major neuropsychiatric disorder with high heritability and complex inheritance. Previously reported linkage between BP and DNA markers in the pericentromeric region of chromosome 18, with a parent-of-origin effect (linkage was present in pedigrees with paternal transmission and absent in pedigrees with exclusive maternal inheritance), has been a focus of interest in human genetics. We reexamined the evidence in one of the largest samples reported to date (1,013 genotyped individuals in 53 unilineal multiplex pedigrees), using 10 highly polymorphic markers and a range of parametric and nonparametric analyses. There was no evidence for significant linkage between BP and chromosome 18 pericentromeric markers in the sample as a whole, nor was there evidence for significant parent-of-origin effect (pedigrees with paternal transmission were not differentially linked to the implicated chromosomal region). Two-point LOD scores and single-locus sib-pair results gave some support for suggestive linkage, but this was not substantiated by multilocus analysis, and the results were further tempered by multiple test effects. We conclude that there is no compelling evidence for linkage between BP and chromosome 18 pericentromeric markers in this sample.     

Linkage analysis of von Recklinghausen neurofibromatosis to DNA markers on chromosome 17

Several recent studies indicate that the von Recklinghausen neurofibromatosis (NF1) gene is located near the centromere of chromosome 17 in some families. However, variable expressivity and a very high mutation rate suggest that defects at several different loci could result in phenotypes categorized as NF1. In order to assess this possibility and to map the NF1 gene more precisely, we have used two polymorphic DNA markers from chromosome 17 to screen several pedigrees for linkage to NF1. We ascertained a large Caucasian pedigree (33 individuals sampled, 17 NF1 affected) as well as eight smaller pedigrees and nuclear families (50 individuals sampled, 30 NF1 affected). Here, we report strong evidence of linkage of NF1 to the centromeric marker D17Z1 (maximum lod = 4.42) and a weaker suggestion of linkage to the ERBA1 oncogene (maximum lod = 0.57), both at a recombination fraction of zero. Since obligate cross-overs with NF1 were not observed for either marker in any of the informative families tested, the possibility of NF1 locus heterogeneity is not supported.     

Linkage map of eight human chromosome 11q markers, including DRD2, spanning 60 cM.

We have constructed a linkage map of eight RFLP markers located on chromosome 11q in the region of the dopamine D2 receptor gene (DRD2) recognized by probe hD2G1. Abnormalities in dopaminergic neurotransmission mediated by this receptor have been implicated in several psychiatric disorders. The map was generated using six large reference families (from 294 to 419 individuals per locus), which are largely independent of the CEPH families, primarily using the LINKMAP and ILINK programs of the LINKAGE package of Lathrop and Lalouel. The most likely order and recombination frequencies are: [sequence: see text] The relative order of D11S84-STMY, DRD2-D11S29, and D11S146-INT2 could not be resolved reliably. There were no significant sex differences in recombination frequency. We introduce here a version of LINKMAP adapted to run under distributed parallel processing (LINDA-LINKMAP). Using pairwise analyses, we have also placed D11S421 proximal to this group.     

Autosomal dominant aniridia linked to the chromosome 11p13 markers catalase and D11S151 in a large Dutch family

In a large pedigree with autosomal dominant aniridia, we found close linkage between the aniridia locus AN2 and the markers catalase (CAT) (zeta = 7.27 at theta = 0.00) and D11S151 (zeta = 3.86 at theta = 0.10) flanking the AN2 locus on 11p13. Positive lod scores were also obtained for the 11p13----11p14 markers D11S16 and FSHB with the linkage group CAT/AN2/D11S151. We conclude that the autosomal dominant aniridia in this family is due to a mutation at the AN2 locus on 11p13. We have excluded linkage (zeta less than -2 at theta less than 0.18) between the aniridia and the chromosome 2p25 marker D2S1 (linked to ACP1).     

Linkage analysis of multiple endocrine neoplasia type 1 with INT2 and other markers on chromosome 11

We evaluated linkage between the locus for multiple endocrine neoplasia type 1 (MEN1) and several polymorphic DNA markers on chromosome 11 in a single large pedigree. On the basis of the finding of a basic fibroblast growth factor (bFGF)-like substance circulating in plasma of MEN1 patients, we chose a bFGF-related gene known to be localized to 11q13 as one of the markers. This gene locus, INT2, was found to be closely linked to the MEN1 gene. Pairwise and multipoint analyses with INT2 confirm the recent finding by C. Larsson et al. (1988, Nature (London) 332: 85-87) of MEN1 linkage to another marker, skeletal muscle glycogen phosphorylase, at 11q13.     

Linkage of infantile Bartter syndrome with sensorineural deafness to chromosome 1p.

Bartter syndrome (BS) is a family of disorders manifested by hypokalemic hypochloremic metabolic alkalosis with normotensive hyperreninemic hyperaldosteronism. We evaluated a unique, inbred Bedouin kindred in which sensorineural deafness (SND) cosegregates with an infantile variant of the BS phenotype. Using a DNA-pooling strategy, we screened the human genome and successfully demonstrated linkage of this unique syndrome to chromosome 1p31. The genes for two kidney-specific chloride channels and a sodium/hydrogen antiporter, located near this region, were excluded as candidate genes. Although the search for the disease-causing gene in this family continues, this linkage further demonstrates the genetic heterogeneity of BS. In addition, the cosegregation of these phenotypes allows us to postulate that a single genetic alteration may be responsible for the SND and the BS phenotype. The identification and characterization of this gene would lead to a better understanding of the normal physiology of the kidney and the inner ear.     

Linkage of Wolfram syndrome to chromosome 4p16.1 and evidence for heterogeneity.

Wolfram syndrome (DIDMOAD syndrome; MIM 222300) is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and bilateral optic atrophy. Previous linkage analysis of multiply affected families indicated that the gene for Wolfram syndrome is on chromosome 4p, and it produced no evidence for locus heterogeneity. We have investigated 12 U.K. families with Wolfram syndrome, and we report confirmation of linkage to chromosome 4p, with a maximum two-point LOD score of 4.6 with DRD5, assuming homogeneity, and of 5.1, assuming heterogeneity. Overlapping multipoint analysis using six markers at a time produced definite evidence for locus heterogeneity: the maximum multipoint LOD score under homogeneity was <2, whereas when heterogeneity was allowed for an admixture a LOD of 6.2 was obtained in the interval between D4S432 and D4S431, with the peak close to the marker D4S3023. One family with an atypical phenotype was definitely unlinked to the region. Haplotype inspection of the remaining 11 families, which appear linked to chromosome 4p and had typical phenotypes, revealed crossover events during meiosis, which also placed the gene in the interval D4S432 and D4S431. In these families no recombinants were detected with the marker D4S3023, which maps within the same interval.     

Linkage of a gene for familial hypobetalipoproteinemia to chromosome 3p21.1-22

Familial hypobetalipoproteinemia (FHBL) is an apparently autosomal dominant disorder of lipid metabolism characterized by less than fifth percentile age- and sex-specific levels of apolipoprotein beta (apobeta) and low-density lipoprotein-cholesterol. In a minority of cases, FHBL is due to truncation-producing mutations in the apobeta gene on chromosome 2p23-24. Previously, we reported on a four-generation FHBL kindred in which we had ruled out linkage of the trait to the apobeta gene. To locate other loci containing genes for low apobeta levels in the kindred, a genomewide search was conducted. Regions on 3p21.1-22 with two-point LOD scores >1.5 were identified. Additional markers were typed in the region of these signals. Two-point LOD scores in the region of D3S2407 increased to 3.35 at O = 0. GENEHUNTER confirmed this finding with an nonparametric multipoint LOD score of 7.5 (P=.0004). Additional model-free analyses were conducted with the square root of the apobeta level as the phenotype. Results from the Loki and SOLAR programs further confirmed linkage of FHBL to 3p21.1-22. Weaker linkage to a region near D19S916 was also indicated by Loki and SOLAR. Thus, a heretofore unidentified genetic susceptibility locus for FHBL may reside on chromosome 3.     

Erbb is linked to the alpha-globin locus on mouse chromosome 11.

A fragment of the human gene for c-erb-B was used to map homologous sequences in mice. Analysis of somatic cell hybrids and recombinant inbred and congenic mouse strains indicated that this gene, designated Erbb, is closely linked to the gene for alpha-globin on mouse chromosome 11. Several genes controlling hematopoietic differentiation map to mouse chromosome 11.     

Linkage study on dieldrin resistance and an inversion on the second chromosome of Anopheles stephensi.

In a study on the linkage between the gene for dieldrin resistance and an inversion on the second chromosome in Anopheles stephensi, the two factors were found to assort independently. As dieldrin resistance can be assigned either to the third chromosome, or to a position on the second chromosome more than 50 cross-over units from the inversion.