Significant evidence for linkage of mite-sensitive childhood asthma to chromosome 5q31-q33 near the interleukin 12 B locus by a genome-wide search in Japanese families

Childhood-onset asthma is frequently found in association with atopy. Although asthmatic children may develop IgE antibodies against variety of allergens, asthma is associated primarily with allergy to house-dust mites, molds, or other allergens. In this study, we conducted a genome-wide linkage search in 47 Japanese families (197 members) with more than two mite-sensitive atopic asthmatics (65 affected sib-pairs) using 398 markers. Multipoint linkage analysis was carried out for atopic asthma as a qualitative trait using the MAPMAKER/SIB program. We observed significant evidence for linkage with maximum lod scores (MLS) of 4.8 near the interleukin 12 B gene locus on chromosome 5q31-q33. In addition, suggestive evidence on 4q35 with MLS = 2.7 and on 13q11 with MLS = 2.4 was obtained. The other possible linkage regions included 6p22-p21.3 (MLS = 2.1), 12q21-q23 (MLS = 1.9), and 13q14.1-q14.3 (MLS = 2.0). Many of the linkage loci suggested in this study were at or close to those suggested by genome-wide studies for asthma in Caucasian populations. The present study suggests the contribution of the interleukin 12 B gene or nearby gene(s) to mite-sensitive atopic asthma and a considerable number of genetic variants common across Caucasians and Japanese populations contributing to asthma, although the relative importance of various variants may differ between the groups.     

Suggestive evidence for linkage of schizophrenia to markers on chromosome 13 in Caucasian but not Oriental populations

Previously we reported suggestive evidence for linkage of schizophrenia to markers on chromosome 13q14.1–q32. We have now studied an additional independent sample of 44 pedigrees consisting of 34 Taiwanese, 9 English and 1 Welsh family in an attempt to replicate this finding. Narrow and broad models based on Research Diagnostic Criteria or the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised, were used to define the schizophrenia phenotype. Under a dominant genetic model, two-point lod scores obtained for most of the markers were negative except that marker D13S122 gave a total lod score of 1.06 (θ = 0.2, broad model). As combining pedigrees from different ethnic origins may be inappropriate, we combined this replication sample and our original sample, and then divided the total sample into Caucasian (English and Welsh pedigrees) and Oriental (Taiwanese and Japanese pedigrees) groups. The Caucasian pedigrees produced maximized admixture two-point lod scores (A-lod) of 1.41 for the marker D13S119 (θ = 0.2, α = 1.0) and 1.54 for D13S128 (θ = 0, α = 0.3) with nearby markers also producing positive A-lod scores. When five-point model-free linkage analysis was applied to the Caucasian sample, a maximum lod score of 2.58 was obtained around the markers D13S122 and D13S128, which are located on chromosome 13q32. The linkage results for the Oriental group were less positive than the Caucasian group. Our results again suggest that there is a potential susceptibility locus for schizophrenia on chromosome 13q14.1–q32, especially in the Caucasian population. Received: 13 September 1996     

Does haplotype diversity predict power for association mapping of disease susceptibility?

Atopy is an IgE-mediated condition known to aggregate in families and is a major risk factor for asthma. As part of the Collaborative Study on the Genetics of Asthma (CSGA), a genome-wide scan for atopy, defined by skin sensitivity to one or more common environmental allergens, was conducted in 287 CSGA families (115 African American, 138 Caucasian and 34 Hispanic). Using a nonparametric genetic analysis approach, two regions were observed in the sample of all families that yielded multipoint lod scores >1.5 (chromosome 11q, lod=1.55 between D11S1986 and D11S1998; chromosome 20p between D20S473 and D20S604, lod=1.54). Modeling that included multiple genomic positions simultaneously indicated that four chromosomal regions accounted for the majority of evidence for linkage in the combined families. These four regions are on chromosomes 10p near D10S1412 (lod=0.94), 11q near D11S1986 (lod=1.76), 17q near D17S784 (lod=0.97) and 20p near D20S473 (lod=1.74). In the subset of pedigrees giving positive evidence for linkage on chromosome 11q, the evidence for linkage increased by lod scores greater than one in four other chromosomal regions: 5q (D5S1480, lod=1.65), 8p (D8S1113, lod=1.60), 12p (D12S372, lod=1.54) and 14q (D14S749, lod=1.70). These results suggest that several regions may harbor genes contributing to the risk for atopy and these may interact with one another in a complex manner.This work is published on behalf of the NHLBI Collaborative Study on the Genetics of Asthma     

A third gene locus for tuberous sclerosis is closely linked to the phenylalanine hydroxylase gene locus

Summary Following the observation of a patient suffering from tuberous sclerosis (TSC) with a de novo reciprocal translocation t(3;12)(p26.3;q23.3), we have undertaken a linkage study in 15 TSC families using polymorphic DNA markers neighbouring the chromosome breakpoints. Significant lod scores have been obtained for markers D12S7 (z _max=2.34, =0.14) and PAH (phenylalanine hydroxylase) (z _max=4.34, =0.0). In multipoint linkage analysis, the peak lod score was 4.56 at the PAH gene locus. These data suggest the existence of a third gene locus for TSC (TSC3) on chromosome 12q22-24.1. The regions that have been found to be linked to TSC in different families map to the positions of three enzymes, phenylalanine hydroxylase (12q22-24), tyrosinase (11q14-22), and dopamine-beta-hydroxylase (9q34), all of which are involved in the conversion of phenylalanine to catecholamine neurotransmitters or melanin. Disorders of these biochemical pathways might be involved in the pathogenesis of TSC.     

Localisation of a gene for Papillon-Lefèvre syndrome to chromosome 11q14–q21 by homozygosity mapping

Papillon-Lefèvre syndrome is an autosomal recessively inherited palmoplantar keratoderma of unknown aetiology associated with severe periodontitis leading to premature loss of dentition. Three consanguineous families, two of Turkish and one of German origin, and three multiplex families, one of Ethiopian and two of German origin, with 11 affected and 6 unaffected siblings in all were studied. A targeted genome search was initially attempted to several candidate gene regions but failed to demonstrate linkage. Therefore a genome-wide linkage scan using a combination of homozygosity mapping and traditional linkage analysis was undertaken. Linkage was obtained with marker D11S937 with a maximum two-point lod score of Z _max = 6.1 at recombination fraction θ = 0.00 on chromosome 11q14–q21 near the metalloproteinase gene cluster. Multipoint likelihood calculations gave a maximum lod score of 7.35 between D11S901 and D11S1358. A 9.2-cM region homozygous by descent in the affected members of the three consanguineous families lies between markers D11S1989 and D11S4176 harbouring the as yet unknown Papillon-Lefèvre syndrome gene. Haplotype analyses in all the families studied support this localisation. This study has identified a further locus harbouring a gene for palmoplantar keratoderma and one possibly involved in periodontitis. Received: 19 July 1997 / Accepted: 22 August 1997     

Linkage studies in X-linked Alport's syndrome

Summary Four kindreds segregating for Alport's syndrome (ASLN) compatible with a X-linked inheritance were studied for linkage with polymorphic markers of the human X chromosome. No recombinant was observed between the ASLN locus and the DXS101 and DXS94 loci, the maximum lod scores were z=3.93 and 3.50 respectively. Linkage data between the ASLN locus and the other genetic markers used in the present study are in keeping with the assignment of the mutation to the proximal Xq arm.     

Choroideremia: linkage analysis with physically mapped close DNA-markers

Summary We report linkage studies in 18 choroideremia (TCD) families using four closely linked polymorphic markers. Probe pZ11, which is known to be deleted in several unrelated patients with TCD, showed no recombinations (z _max 15.63 at = 0.00). In contrast, one recombination was observed with DXS367, which is also physically very close to TCD. Loci DXS95 and DXYS69 each showed more than one recombination with TCD. Moreover, these analyses revealed a double crossover between TCD and DXYS1, changing the previously reported very close linkage to a recombination fraction of 0.04 with a lod score of 9.93. Multipoint linkage analysis placed TCD proximal to DXS95-DXYS69 and very close to DXS367-pZ11 with almost identical multipoint lod score maxima either proximal to DXS367 (z _max= 23.43) or proximal to pZ11 (z _max=23.36). These results provide a refined linkage map around TCD and will also be useful in DNA diagnostics of the disease.     

Determining the linkage of disease-resistance genes to molecular markers: the LOD-SCORE method revisited with regard to necessary sample sizes

Some approaches to molecular marker-assisted linkage detection for a dominant disease-resistance trait based on a segregating F₂ population are discussed. Analysis of two-point linkage is carried out by the traditional measure of maximum lod score. It depends on (1) the maximum-likelihood estimate of the recombination fraction between the marker and the disease-resistance gene locus, (2) the observed absolute frequencies, and (3) the unknown number of tested individuals. If one replaces the absolute frequencies by expressions depending on the unknown sample size and the maximum-likelihood estimate of recombination value, the conventional rule for significant linkage (maximum lod score exceeds a given linkage threshold) can be resolved for the sample size. For each sub-population used for linkage analysis [susceptible (= recessive) individuals, resistant (= dominant) individuals, complete F₂] this approach gives a lower bound for the necessary number of individuals required for the detection of significant two-point linkage by the lod-score method.     

Genetic predisposition to familial neuroblastoma: identification of two novel genomic regions at 2p and 12p

OBJECTIVES: The rarity of familial neuroblastoma (NB) has allowed only a few linkage studies, most of which did not show any evidence of linkage to regions involved in somatic alterations or to genes implicated in other neurocristopathies seldom associated with NB. We screened a highly informative family with recurrent NB by genome-wide linkage analysis aimed at identifying chromosomal regions for NB predisposing genes. METHODS: A genome-wide screen was performed using 382 microsatellite markers. Multipoint model-based linkage analysis was carried out under a dominant mode of inheritance for the disease using the 'affected only' approach. RESULTS: Our analysis identified two haplotypes co-segregating with the disease on chromosomes 2p and 12p, and yielded maximum lod-score values of 3.01 (p < 0.0001) for markers on both intervals. CONCLUSIONS: Evidence of linkage was reported at 16p in North American families, whereas our studies excluded this interval and indicated other loci for disease predisposition, thus confirming the remarkable genetic heterogeneity of NB. These results suggest an oligogenic inheritance in NB involving more loci in genetic determination of the disease.     

Linkage and association to candidate regions in Swedish atopic dermatitis families

We have studied, in 406 families with at least two siblings affected with atopic dermatitis (in total 1514 individuals) from the Swedish population, linkage and association to five chromosomal regions (2q35, 5q31-33, 6p21, 11q13 and 14q11) previously implicated in atopic diseases. The region on 14q11 gave evidence for linkage to atopic dermatitis (NPL-score: 2.36, P<0.009). In the 11q13 region, there was a clear association to an intragenic marker in the beta-subunit of the high-affinity IgE receptor for raised allergen-specific serum IgE levels (P<0.009). When a quantitative variable for the severity of atopic dermatitis was studied, evidence was found in favour of linkage to the 5q31-33 region, with the highest Z-score (2.06) close to the marker D5S458 (P<0.005).     

Autosomal recessive nonsyndromic deafness locus DFNB63 at chromosome 11q13.2–q13.3

A genome wide linkage analysis of nonsyndromic deafness segregating in a consanguineous Pakistani family (PKDF537) was used to identify DFNB63, a new locus for congenital profound sensorineural hearing loss. A maximum two-point lod score of 6.98 at θ = 0 was obtained for marker D11S1337 (68.55 cM). Genotyping of 550 families revealed three additional families (PKDF295, PKDF702 and PKDF817) segregating hearing loss linked to chromosome 11q13.2-q13.3. Meiotic recombination events in these four families define a critical interval of 4.81 cM bounded by markers D11S4113 (68.01 cM) and D11S4162 (72.82 cM), and SHANK2, FGF-3, TPCN2 and CTTN are among the candidate genes in this interval. Positional identification of this deafness gene should reveal a protein necessary for normal development and/or function of the auditory system.     

Refinement of the Locus for Autosomal Dominant Hereditary Gingival Fibromatosis (GINGF) to a 3.8-cM Region on 2p21

Hereditary gingival fibromatosis (HGF, MIM 135300; approved gene symbol GINGF) is an oral disease characterized by enlargement of gingiva. Recently, a locus for autosomal dominant HGF has been mapped to an 11-cM region on chromosome 2p21. In the current investigation, we genotyped four Chinese HGF families using polymorphic microsatellite markers on 2p21. The HOMOG test provided evidence for genetic homogeneity, with evidence for linkage in four families (heterogeneity versus homogeneity test HOMOG, χ² = 0.00). A cumulative maximum two-point lod score of 5.04 was produced with marker D2S390 at a recombination frequency of θ = 0 in the four linked families. Haplotype analysis localized the hereditary gingival fibromatosis locus within the region defined by D2S352 and D2S2163. This region overlaps by 3.8 cM with the previously reported HGF region. Single-strand conformation polymorphism and sequence analysis of the coding region of cytochrome P450 1B1 (CYP1B1) excluded it as a likely candidate gene.     

Confirmation of chromosome 7q11 locus for predisposition to intracranial aneurysm

A significant linkage of intracranial aneurysm (IA) has recently been reported to chromosomal region 7q11 (MLS=3.22) in a genomic search of 85 Japanese nuclear families with at least two affected siblings (104 sib pairs). This region contains the elastin gene (ELN, OMIM 130160), which is a functional candidate gene for IA. We have replicated this finding through linkage analyses in 13 extended pedigrees from Utah, comprising 39 IA cases. We genotyped three markers flanking ELN and performed two-point and multipoint parametric analyses, employing simple dominant and recessive models. Analyses utilizing a recessive affecteds-only model yielded significant confirmation of linkage to the region (best evidence, multipoint TLOD=2.34, at D7S2421, corrected P=0.001). This study is the first to confirm the linkage of the 7q11 locus for IA.     

Identification of a New Locus for Autosomal Recessive Charcot–Marie–Tooth Disease with Focally Folded Myelin on Chromosome 11p15

Autosomal recessive Charcot–Marie–Tooth disease type 4B (CMT4B) is a demyelinating hereditary motor and sensory neuropathy characterized by abnormal folding of myelin sheaths. A locus for CMT4B has previously been mapped to chromosome 11q23 in a southern Italian pedigree. We initially excluded linkage in two Tunisian families with CMT4B to chromosome 11q23, demonstrating genetic heterogeneity within the CMT4B phenotype. Subsequently, using homozygosity mapping and linkage analysis in the largest Tunisian pedigree, we mapped a new locus to chromosome 11p15. A maximum two-point lod score of 6.05 was obtained with the marker D11S1329. Recombination events refined the CMT4B locus region to a 5.6-cM interval between markers D11S1331 and D11S4194. The second Tunisian CMT4B family was excluded from linkage to the new locus, demonstrating the existence of at least a third locus for the CMT4B phenotype.     

Evidence for heterogeneity in facioscapulohumeral muscular dystrophy (FSHD)

Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive primary disease of muscle which is usually inherited as an autosomal dominant disorder. FSHD has been localized to the long arm of chromosome 4, specifically to the 4q3.5-qter region. Initially published linkage studies showed no evidence for heterogeneity in FSHD. In the present study we have examined individuals in seven FSHD families. Two-point lod scores show significant evidence for linkage for D4S163 (lod score 3.04 at recombination fraction .21) and D4S139 (lod score 3.84 at recombination fraction .20). D4S171 also gave a positive score (lod score 2.56 at recombination fraction .24). Significant evidence for heterogeneity was found for each of the three markers. Multipoint linkage analysis in this region resulted in a peak multipoint lod score of 6.47. The multipoint analysis supported the two-point studies with odds of 20:1 showing linkage and heterogeneity over linkage and homogeneity. Five of the seven families gave a posterior probability of >95% of being of the linked type, while two families appeared unlinked to this region of 4q (P < .01%). Individuals in the two unlinked families met the clinical criteria for the diagnosis of FSHD, including facial weakness, clavicular flattening, scapula winging, proximal muscle weakness, and myopathic changes on muscle biopsies without inflammatory or mitochondrial pathology. This study demonstrates genetic heterogeneity in FSHD and has important implications for both genetic counseling and the elucidation of the etiology of FSHD.     

Exclusion of two candidate pigment loci,c and b,part of chromosome 11p,and 33 random polymorphic markers as the locus for tyrosinase-positive oculocutaneous albinism

The locus for Tyrosinase-Positive Oculocutaneous Albinism (ty-pos OCA) has not yet been localised. The search for the ty-pos OCA locus has included a search for linkage to candidate pigment loci and a candidate chromosomal region, as well as a random search using highly polymorphic markers in 42 families, including 271 individuals of whom 79 are affected. The lod scores for the tyrosinase (TYR) locus (11q14–q21), homologous to the albino locus, c, in the mouse and the CAS2/TRP1 locus (9p22-pter), homologous to the brown locus, b, in the mouse were -5.89 and -7.22, respectively, at a recombination fraction of =0.01, thus excluding them from being the ty-pos OCA locus. In the candidate chromosomal region, 11p, four loci (probes) were tested, SAA (pSAA82), CALC (pHC36), HBB (Gamma-globin haplotype) and an AC repeat polymorphism at the Wilm's Tumour locus (WT1). A portion of 11p was excluded with the following lod scores: pSAA82 lod=-2.05 at =0.10; pHC36 lod=-3.87 at =0.05; gamma-globin haplotype lod=-2.80 at =0.10; and WT1 lod=-2.34 at =0.10. Thirty-three polymorphic markers randomly distributed on 13 different chromosomes were all excluded from close linkage to ty-pos OCA.     

Gender-influenced obesity QTLs identified in a cross involving the KK type II diabetes-prone mouse strain

The inheritance of adiposity and related traits has been investigated in the obese, diabetes-prone KK/HlLt (KK) and the lean, normoglycemic C57BL/6J (B6) mouse strains, their F₁ hybrids, and a large intercross generation. Adiposity index (AI) was defined as the sum of four fat depot weights divided by body weight. Both male and female KK mice were obese, but AI values averaged twofold higher in females than in males. In contrast, B6 females were slightly more lean than males. A genome-wide search revealed several qualitative trait loci (QTLs) affecting AI. The proximal region of Chromosome (Chr) 9 has a large effect on AI, with a much stronger effect in females (lod = 6.3) than in males (lod = 2.7). The data for females fit a model in which a dominant allele from KK increases AI by 30%, with the lod score peak falling between markers D9Mit66 and D9Mit328. This QTL has large effects on inguinal and mesenteric fat pad weights, with smaller effects on gonadal and retroperitoneal fat pads. The region of Chr 9 containing this QTL has extensive homology to human Chr 11q. An X-linked QTL affecting AI was evident in males (lod = 3.77), but not females (lod = 0.7). Exclusion of mesenteric fat from male AI resulted in an increased lod score (lod = 5.0) at 8 cM distal to DXMit166. A suggestive AI QTL (lod = 4.2), differentially affecting males, was localized to Chr 18 near the glucocorticoid receptor locus. A region of Chr 7 had a strong effect on body weight (lod = 6.9), a significant effect on inguinal fat% (lod = 4.4), and a suggestive effect on AI in females (lod = 4.1). Plasma leptin levels were associated with genotypes on Chr 9 (lod = 5.9) and Chr 7 (lod = 4.2). A region of Chr 1 had a suggestive effect on fasted blood glucose (lod = 3.6). Received: 23 March 1999 / Accepted: 2 June 1999     

Linkage and allelic association of chromosome 5 cytokine cluster genetic markers with atopy and asthma associated traits

Linkage and association of polymorphic markers in the chromosome 5q31-q33 cytokine cluster to atopy and asthma associated phenotypes have been reported by a number of groups. To investigate this region, 29 polymorphic markers were used to genotype a combined set of 233 families. These markers were ordered based upon the genetic data, supplemented by published genetic and physical maps. Significant two-point linkage was observed for asthma (most significant marker IRF1, P = 0.0002) and atopy (CD14SNP, P = 0.0001). Allelic association was observed between D5S463 and atopy (P = 0.002) and the skin prick test index (P = 0.04). The data support the possibility of three asthma/atopy loci in the 5q31-q33 region, each with a relatively small effect.     

Autosomal recessive juvenile onset cataract associated with mutation in BFSP1

A genome wide scan in a consanguineous family of Indian origin with autosomal recessive developmental cataracts was performed by two-point linkage analysis with 382 microsatellite markers. It showed linkage to markers on chromosome 20q, between D20S852 and D20S912, with a maximum lod score of 5.4 obtained with D20S860. This region encompasses the beaded filament structural protein 1 (BFSP1) gene. Direct sequencing revealed a 3343 bp deletion including exon 6 (c.736-1384_c.957-66 del) predicted to result in a shift of the open reading frame. This mutation was absent in 50 control individuals from south India. This is the first report of a mutation in the BFSP1 gene associated with human inherited cataracts. This further increases the genetic heterogeneity of inherited cataracts and provides clues as to the importance of BFSP1 in the cell biology of intermediate filaments and their role in the eye lens.     

The autosomal dominant familial exudative vitreoretinopathy locus maps on 11q and is closely linked to D11S533.

Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is a hereditary disorder characterized by the incomplete vascularization of the peripheral retina. The primary biochemical defect in adFEVR is unknown. The adFEVR locus has tentatively been assigned to 11q by linkage studies. We report the results of an extended multipoint linkage analysis of two families with adFEVR by using five markers (INT2, D11S533, D11S527, D11S35, and CD3D) from 11q13-q23. Pairwise linkage data obtained in the two families were rather similar and hence have not provided evidence for genetic heterogeneity. The highest complied two-point lod score (3.67, at a recombination fraction of .07) was obtained for the disease locus versus D11S533. Multipoint analyses showed that the adFEVR locus maps most likely, with a maximum location score of over 20, between D11S533/D11S527 and D11S35, at recombination rates of .147 and .104, respectively. Close linkage without recombination (maximum lod score 11.26) has been found between D11S533 and D11S527.