Chromosome-12 Mapping of Late-Onset Alzheimer Disease among Caribbean Hispanics

Linkage to chromosome 12p for familial Alzheimer disease (AD) has been inconsistent. Using 35 markers near the centromere of chromosome 12, we investigated 79 Caribbean Hispanic families with AD. Two-point linkage analysis using affected sib pairs yielded LOD scores of 3.15 at D12S1623 and 1.43 at D12S1042. The LOD score at D12S1623 decreased to 1.62 in families with late-onset (age >65 years) AD (LOAD), but the LOD score at D12S1042 was unchanged. Among families negative for the apolipoprotein E (APOE-epsilon 4) allele, the LOD score for D12S1623 was lower (1.01), whereas that for D12S1042 increased to 1.73. Among families positive for the APOE-epsilon 4 allele, none of the LOD scores reached 1. Multipoint affected-relative-pair analysis showed peaks at D12S1623 (nonparametric linkage [NPL] score 1.52; P=.028) and near D12S1042, at D12S1057 (NPL score 1.57; P=.027). NPL scores for both D12S1623 and D12S1057 increased in families affected with LOAD, but, in APOE-epsilon 4-negative families, only scores for the region flanking D12S1623 remained elevated (NPL score 1.74; P=.013). This study of Caribbean Hispanics with familial AD extends and provides modest evidence of linkage to loci on chromosome 12p. Linkage varied by age at onset of AD and by the presence or absence of the APOE-epsilon 4 allele.     

High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q11-12

Epidemiological studies have shown that genetic factors contribute to the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC). Recent genome scans and replication studies have identified replicated linkage between CD and a locus on chromosome 16 (the IBD1 locus), replicated linkage between IBD (especially UC) and a locus on chromosome 12q (the IBD2 locus), and replicated linkage between IBD (especially CD) and a locus on chromosome 6p (the IBD3 locus). Since the estimated locus-specific lambdas values for the regions of replicated linkage do not account for the overall lambdas in CD, and since the published genome scans in IBD show at least nominal evidence for linkage to regions on all but two chromosomes, we performed an independent genome scan using 751 microsatellite loci in 127 CD-affected relative pairs from 62 families. Single-point nonparametric linkage analysis using the GENEHUNTER-PLUS program shows evidence for linkage to the adjacent D14S261 and D14S283 loci on chromosome 14q11-12 (LOD = 3.00 and 1.70, respectively), and the maximal multipoint LOD score is observed at D14S261 (LOD = 3.60). In the multipoint analysis, nominal evidence for linkage (P<.05) is observed near D2S117 (LOD = 1.25), near D3S3045 (LOD = 1.31), between D7S40 and D7S648 (LOD = 0.91), and near D18S61 (LOD = 1.15). Our finding of significant linkage to D14S261 and the finding of suggestive linkage to the same locus in an independent study (multipoint LOD = 2.8) satisfies criteria for confirmed linkage, so we propose that the region of interest on chromosome 14q11-12 should be designated the IBD4 locus.     

Linkage and association between inflammatory bowel disease and a locus on chromosome 12.

Genetic epidemiological studies have shown that genetic factors are important in the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD), and ulcerative colitis (UC). A genome screen in the United Kingdom found linkage of IBD to a 41-cM region of chromosome 12, surrounding D12S83. We aimed to replicate this linkage and to narrow the region of interest. Nonparametric linkage analyses at microsatellites surrounding D12S83 were performed in 122 North American Caucasian families containing 208 genotyped IBD-affected relative pairs. Transmission/disequilibrium tests (TDTs) were also performed. We confirmed that IBD is linked to chromosome 12 (peak GENEHUNTER-PLUS LOD* score 2.76 [P = .00016] between D12S1724 and D12S90). The evidence for linkage is contributed by both the group of CD-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.79 [P = .0021] between D12S1724 and D12S90) and the group of UC-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.82 [P = .0019] at D12S335). The TDT is positive at the D12S83 locus (global chi2 = 16.41, 6 df, P = .012). In conclusion, we have independently confirmed linkage of IBD to the chromosome 12 region that we investigated. A positive TDT at D12S83 suggests that we have greatly narrowed the chromosome 12 region that contains an IBD locus.     

Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity

Apolipoprotein E (APOE) is the only confirmed susceptibility gene for late-onset Alzheimer disease (AD). In a recent genomic screen of 54 families with late-onset AD, we detected significant evidence for a second late-onset AD locus located on chromosome 12 between D12S373 and D12S390. Linkage to this region was strongest in 27 large families with at least one affected individual without an APOE-4 allele, suggesting that APOE and the chromosome 12 locus might have independent effects. We have since genotyped several additional markers across the region, to refine the linkage results. In analyzing these additional data, we have addressed the issue of heterogeneity in the data set by weighting results by clinical and neuropathologic features, sibship size, and APOE genotype. When considering all possible affected sib pairs (ASPs) per nuclear family, we obtained a peak maximum LOD score between D12S1057 and D12S1042. The magnitude and location of the maximum LOD score changed when different weighting schemes were used to control for the number of ASPs contributed by each nuclear family. Using the affected-relative-pair method implemented in GENEHUNTER-PLUS, we obtained a maximum LOD score between D12S398 and D12S1632, 25 cM from the original maximum LOD score. These results indicate that family size influences the location estimate for the chromosome 12 AD gene. The results of conditional linkage analysis by use of GENEHUNTER-PLUS indicated that evidence for linkage to chromosome 12 was stronger in families with affected individuals lacking an APOE-4 allele; much of this evidence came from families with affected individuals with neuropathologic diagnosis of dementia with Lewy bodies (DLB). Taken together, these results indicate that the chromosome 12 locus acts independently of APOE to increase the risk of late-onset familial AD and that it may be associated with the DLB variant of AD.     

Genomewide Linkage Analysis of Stature in Multiple Populations Reveals Several Regions with Evidence of Linkage to Adult Height

Genomewide linkage analysis has been extremely successful at identification of the genetic variation underlying single-gene disorders. However, linkage analysis has been less successful for common human diseases and other complex traits in which multiple genetic and environmental factors interact to influence disease risk. We hypothesized that a highly heritable complex trait, in which the contribution of environmental factors was relatively limited, might be more amenable to linkage analysis. We therefore chose to study stature (adult height), for which heritability is approximately 75%-90% (Phillips and Matheny 1990; Carmichael and McGue 1995; Preece 1996; Silventoinen et al. 2000). We reanalyzed genomewide scans from four populations for which genotype and height data were available, using a variance-components method implemented in GENEHUNTER 2.0 (Pratt et al. 2000). The populations consisted of 408 individuals in 58 families from the Botnia region of Finland, 753 individuals in 183 families from other parts of Finland, 746 individuals in 179 families from Southern Sweden, and 420 individuals in 63 families from the Saguenay-Lac-St.-Jean region of Quebec. Four regions showed evidence of linkage to stature: 6q24-25, multipoint LOD score 3.85 at marker D6S1007 in Botnia (genomewide P<.06), 7q31.3-36 (LOD 3.40 at marker D7S2195 in Sweden, P<.02), 12p11.2-q14 (LOD 3.35 at markers D12S10990-D12S398 in Finland, P<.05) and 13q32-33 (LOD 3.56 at markers D13S779-D13S797 in Finland, P<.05). In a companion article (Perola et al. 2001 [in this issue]), strong supporting evidence is obtained for linkage to the region on chromosome 7. These studies suggest that highly heritable complex traits such as stature may be genetically tractable and provide insight into the genetic architecture of complex traits.     

The PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval

Recently, a new locus (PARK8) for autosomal dominant parkinsonism has been identified in one large Japanese family. Linkage has been shown to a 16-cM centromeric region of chromosome 12, between markers D12S1631 and D12S339. We tested 21 white families with Parkinson disease and an inheritance pattern compatible with autosomal dominant transmission for linkage in this region. Criteria for inclusion were at least three affected individuals in more than one generation. A total of 29 markers were used to saturate the candidate region. One hundred sixty-seven family members were tested (84 affected and 83 unaffected). Under the assumption of heterogeneity and through use of an affecteds-only model, a maximum multipoint LOD score of 2.01 was achieved in the total sample, with an estimated proportion of families with linkage of 0.32. This LOD score is significant for linkage in a replication study and corresponds to a P value of.0047. Two families (family A [German Canadian] and family D [from western Nebraska]) reached significant linkage on their own, with a combined maximum multipoint LOD score of 3.33, calculated with an affecteds-only model (family A: LOD score 1.67, P=.0028; family D: LOD score 1.67, P=.0028). When a penetrance-dependent model was calculated, the combined multipoint LOD score achieved was 3.92 (family A: LOD score 1.68, P=.0027; family D: LOD score 2.24, P=.0007). On the basis of the multipoint analysis for the combined families A and D, the 1-LOD support interval suggests that the most likely disease location is between a CA repeat polymorphism on genomic clone AC025253 (44.5 Mb) and marker D12S1701 (47.7 Mb). Our data provide evidence that the PARK8 locus is responsible for the disease in a subset of families of white ancestry with autosomal dominant parkinsonism, suggesting that it could be a more common locus.     

A genomewide screen for autism-spectrum disorders: evidence for a major susceptibility locus on chromosome 3q25-27

To identify genetic loci for autism-spectrum disorders, we have performed a two-stage genomewide scan in 38 Finnish families. The detailed clinical examination of all family members revealed infantile autism, but also Asperger syndrome (AS) and developmental dysphasia, in the same set of families. The most significant evidence for linkage was found on chromosome 3q25-27, with a maximum two-point LOD score of 4.31 (Z(max )(dom)) for D3S3037, using infantile autism and AS as an affection status. Six markers flanking over a 5-cM region on 3q gave Z(max dom) >3, and a maximum parametric multipoint LOD score (MLS) of 4.81 was obtained in the vicinity of D3S3715 and D3S3037. Association, linkage disequilibrium, and haplotype analyses provided some evidence for shared ancestor alleles on this chromosomal region among affected individuals, especially in the regional subisolate. Additional potential susceptibility loci with two-point LOD scores >2 were observed on chromosomes 1q21-22 and 7q. The region on 1q21-22 overlaps with the previously reported candidate region for infantile autism and schizophrenia, whereas the region on chromosome 7q provided evidence for linkage 58 cM distally from the previously described autism susceptibility locus (AUTS1).     

Evidence for asthma susceptibility genes on chromosome 11 in an African-American population

Initial genome-wide scan data provided suggestive evidence for linkage of the asthma phenotype in African-American (AA), but not Caucasian, families to chromosome 11q markers (peak at D11S1985; LOD=2). To refine this region, mapping analysis of 91 AA families (51 multiplex families and 40 asthmatic case-parent trios) was performed with an additional 17 markers flanking the initial peak linkage marker. Multipoint analyses of the 51 multiplex families yielded significant evidence of linkage with a peak non-parametric linkage score of 4.38 at marker D11S1337 (map position 68.6 cM). Furthermore, family-based association and transmission disequilibrium tests conducted on all 91 families showed significant evidence of linkage in the presence of disequilibrium for several individual markers in this region. A putative susceptibility locus was estimated to be at map position 70.8 cM with a confidence interval spanning the linkage peak. Evidence from both linkage and association analyses suggest that this region of chromosome 11 contains one or more susceptibility genes for asthma in these AA families.     

Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2

Birt-Hogg-Dubé syndrome (BHD), an inherited autosomal genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal neoplasia, lung cysts, and spontaneous pneumothorax. To identify the BHD locus, we recruited families with cutaneous lesions and associated phenotypic features of the BHD syndrome. We performed a genomewide scan in one large kindred with BHD and, by linkage analysis, localized the gene locus to the pericentromeric region of chromosome 17p, with a LOD score of 4.98 at D17S740 (recombination fraction 0). Two-point linkage analysis of eight additional families with BHD produced a maximum LOD score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within a <4-cM distance between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to chromosome 17p, suggesting genetic heterogeneity for BHD. The BHD locus lies within chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy-number repeat elements, is unstable and that is associated with a number of diseases. Identification of the gene for BHD may reveal a new genetic locus responsible for renal neoplasia and for lung and hair-follicle developmental defects.     

Autosomal dominant avascular necrosis of femoral head in two Taiwanese pedigrees and linkage to chromosome 12q13

Avascular necrosis of the femoral head (ANFH) is a debilitating disease that commonly leads to destruction of the hip joint in adults. The etiology of ANFH is unknown, but previous studies have indicated that heritable thrombophilia (increased tendency to form thrombi) and hypofibrinolysis (reduced ability to lyse thrombi), alcohol intake, and steroid use are risk factors for ANFH. We recently identified two families with ANFH showing autosomal dominant inheritance. By applying linkage analysis to a four-generation pedigree, we excluded linkage between the family and three genes related to thrombophilia and hypofibrinolysis: protein C, protein S, and plasminogen activator inhibitor. Furthermore, by a genomewide scan, a significant two-point LOD score of 3.45 (recombination fraction [theta] = 0) was obtained between the family with ANFH and marker D12S85 on chromosome 12. High-resolution mapping was conducted in a second family with ANFH and replicated the linkage to D12S368 (pedigree I: LOD score 2.47, theta = 0.05; pedigree II: LOD score 2.81, theta = 0.10). When an age-dependent-penetrance model was applied, the combined multipoint LOD score was 6.43 between D12S1663 and D12S85. Thus, we mapped the candidate gene for autosomal dominant ANFH to a 15-cM region between D12S1663 and D12S1632 on chromosome 12q13.     

A genome-wide linkage scan for 25-OH-D(3) and 1,25-(OH)2-D3 serum levels in asthma families

To identify genome regions linked to serum vitamin D metabolites we analyzed 25-OH-D(3) and 1,25-(OH)(2)-D(3) levels from 947 participants of a family study recruited for asthma. From these individuals data were available from a previous genome scan that included 364 autosomal microsatellite marker. 25-OH-D(3) levels showed a heritability of 80% in these families while 1,25-(OH)(2)-D(3) reached only 30%. Genome-wide linkage using variance component analysis showed increased LOD scores for 25-OH-D(3) at marker D1S2815 (unadjusted LOD 2.9), D2S2153 (LOD 3.4), D5S2017 (LOD 2.5), D6S260 (LOD 2.1) and D17S1824 (2.5). In contrast, the maximum LOD score for 1,25-(OH)(2)-D(3) level was only 1.2 at marker D17S926. We conclude that only 25-OH-D(3) serum levels are under genetic control where several genes are involved. The lead linkage region does not code for enzymes already known in the metabolic pathway of vitamin D and may therefore contain further genes relevant to the regulation of vitamin D serum levels.     

Osteoarthritis-susceptibility locus on chromosome 11q, detected by linkage.

We present a two-stage genomewide scan for osteoarthritis-susceptibility loci, using 481 families that each contain at least one affected sibling pair. The first stage, with 272 microsatellite markers and 297 families, involved a sparse map covering 23 chromosomes at intervals of approximately 15 cM. Sixteen markers that showed evidence of linkage at nominal P相似文献   

A schizophrenia-susceptibility locus at 6q25, in one of the world's largest reported pedigrees

We have completed a genome scan of a 12-generation, 3,400-member pedigree with schizophrenia. Samples from 210 individuals were collected from the pedigree. We performed an "affecteds-only" genome-scan analysis using 43 members of the pedigree. The affected individuals included 29 patients with schizophrenia, 10 with schizoaffective disorders, and 4 with psychosis not otherwise specified. Two sets of white-European allele frequencies were used-one from a Swedish control population (46 unrelated individuals) and one from the pedigree (210 individuals). All analyses pointed to the same region: D6S264, located at 6q25.2, showed a maximum LOD score of 3.45 when allele frequencies in the Swedish control population were used, compared with a maximum LOD score of 2.59 when the pedigree's allele frequencies were used. We analyzed additional markers in the 6q25 region and found a maximum LOD score of 6.6 with marker D6S253, as well as a 6-cM haplotype (markers D6S253-D6S264) that segregated, after 12 generations, with the majority of the affected individuals. Multipoint analysis was performed with the markers in the 6q25 region, and a maximum LOD score of 7.7 was obtained. To evaluate the significance of the genome scan, we simulated the complete analysis under the assumption of no linkage. The results showed that a LOD score >2.2 should be considered as suggestive of linkage, whereas a LOD score >3.7 should be considered as significant. These results suggest that a common ancestral region was inherited by the affected individuals in this large pedigree.     

Major recessive gene(s) with considerable residual polygenic effect regulating adult height: confirmation of genomewide scan results for chromosomes 6, 9, and 12

Segregation and linkage analyses were performed for adult height in a population of 200 Dutch families, each of which was ascertained through a proband with asthma. The best-fit model from the segregation analysis was a major recessive gene with a significant residual polygenic background. Models without a polygenic component were rejected. A genomewide scan was performed, and it confirmed previous linkage results for chromosomes 6q25 (LOD = 3.06, D6S2436), 9p1 (LOD = 2.09, D9S301), and 12q1 (LOD = 1.86, D12S375). Our results provide evidence that a combination of segregation and linkage approaches is valuable in understanding genetic determination of common complex traits.     

In Swedish families with hereditary prostate cancer, linkage to the HPC1 locus on chromosome 1q24-25 is restricted to families with early-onset prostate cancer.

Prostate cancer clusters in some families, and an estimated 5%-10% of all cases are estimated to result from inheritance of prostate cancer-susceptibility genes. We previously reported evidence of linkage to the 1q24-25 region (HPC1) in 91 North American and Swedish families each with multiple cases of prostate cancer (Smith et al. 1996). In the present report we analyze 40 (12 original and 28 newly identified) Swedish families with hereditary prostate cancer (HPC) that, on the basis of 40 markers spanning a 25-cM interval within 1q24-25, have evidence of linkage. In the complete set of families, a maximum two-point LOD score of 1.10 was observed at D1S413 (at a recombination fraction [theta] of.1), with a maximum NPL (nonparametric linkage) Z score of 1.64 at D1S202 (P=.05). The evidence of linkage to this region originated almost exclusively from the subset of 12 early-onset (age <65 years) families, which yielded a maximum LOD score of 2.38 at D1S413 (straight theta=0) and an NPL Z score of 1.95 at D1S422 (P=.03). Estimates from heterogeneity tests suggest that, within Sweden, as many as 50% of early-onset families had evidence of linkage to the HPC1 region. These results are consistent with the hypothesis of linkage to HPC1 in a subset of families with prostate cancer, particularly those with an early age at diagnosis.     

Fine mapping and SNP analysis of positional candidates at the preeclampsia susceptibility locus (PREG1) on chromosome 2

Genome scans in Icelandic, Australian and New Zealand, and Finnish families have localized putative susceptibility loci for preeclampsia/ eclampsia to chromosome 2. The locus mapped in the Australian and New Zealand study (designated PREG1) was thought to be the same locus as that identified in the Icelandic study. In both these studies, two distinct quantitative trait locus (QTL) regions were evident on chromosome 2. Here, we describe our fine mapping of the PREG1 locus and a genetic analysis of two positional candidate genes. Twenty-five additional microsatellite markers were genotyped within the 74-cM linkage region defined by the combined Icelandic and Australian and New Zealand genome scans. The overall position and shape of the localization evidence obtained using nonparametric multipoint analysis did not change from that seen previously in our 10-cM resolution genome scan; two peaks were displayed, one on chromosome 2p at marker D2S388 (107.46 cM) and the other on chromosome 2q at 151.5 cM at marker D2S2313. Using the robust two-point linkage analysis implemented in the Analyze program, all 25 markers gave positive LOD scores with significant evidence of linkage being seen at marker D2S2313 (151.5 cM), achieving a LOD score of 3.37 under a strict diagnostic model. Suggestive evidence of linkage was seen at marker D2S388 (107.46 cM) with a LOD score of 2.22 under the general diagnostic model. Two candidate genes beneath the peak on chromosome 2p were selected for further analysis using public single nucleotide polymorphisms (SNPs) within these genes. Maximum LOD scores were obtained for an SNP in TACR1 (LOD = 3.5) and for an SNP in TCF7L1 (LOD = 3.33), both achieving genome-wide significance. However, no evidence of association was seen with any of the markers tested. These data strongly support the presence of a susceptibility gene on chromosome 2p11-12 and substantiate the possibility of a second locus on chromosome 2q23.     

A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q

Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.     

Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2

The hereditary disorders of peripheral nerve form one of the most common groups of human genetic diseases, collectively called Charcot-Marie-Tooth (CMT) neuropathy. Using linkage analysis we have identified a new locus for a form of CMT that we have called "dominant intermediate CMT" (DI-CMT). A genomewide screen using 383 microsatellite markers showed strong linkage to the short arm of chromosome 19 (maximum LOD score 4.3, with a recombination fraction (straight theta) of 0, at D19S221 and maximum LOD score 5.28, straight theta=0, at D19S226). Haplotype analysis performed with 14 additional markers placed the DI-CMT locus within a 16.8-cM region flanked by the markers D19S586 and D19S546. Multipoint linkage analysis suggested the most likely location at D19S226 (maximum multipoint LOD score 6.77), within a 10-cM confidence interval. This study establishes the presence of a locus for DI-CMT on chromosome 19p12-p13.2.     

Hereditary Vascular Retinopathy, Cerebroretinal Vasculopathy, and Hereditary Endotheliopathy with Retinopathy, Nephropathy, and Stroke Map to a Single Locus on Chromosome 3p21.1-p21.3

We performed a genomewide search for linkage in an extended Dutch family with hereditary vascular retinopathy associated with migraine and Raynaud phenomenon. Patients with vascular retinopathy are characterized by microangiopathy of the retina, accompanied by microaneurysms and telangiectatic capillaries. The genome search, using a high throughput capillary sequencer, revealed significant evidence of linkage to chromosome 3p21.1-p21.3 (maximum pairwise LOD score 5.25, with D3S1578). Testing of two additional families that had a similar phenotype, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke, revealed linkage to the same chromosomal region (combined maximum LOD score 6.30, with D3S1588). Haplotype analysis of all three families defined a 3-cM candidate region between D3S1578 and D3S3564. Our study shows that three autosomal dominant vasculopathy syndromes with prominent cerebroretinal manifestations map to the same 3-cM interval on 3p21, suggesting a common locus.     

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.