Linkage between atopy and the IgE high-affinity receptor gene at 11q13 in atopic dermatitis families

Atopic dermatitis is a common skin disease frequently associated with allergic disorders such as allergic rhinitis and asthma. Controversial linkage findings between atopy and markers at chromosome 11q13 led us to search chromosome 11 for genes conferring susceptibility to atopic dermatitis and atopy. Twelve families were investigated using highly polymorphic markers and a powerful model-free linkage test. Two markers gave evidence for linkage, D11S903 (P = 0.02) and FCER1B (P = 0.005). A two-point lod-score analysis between these two markers revealed significant evidence for linkage (z _max = 4.02 at (θ = 0.0). In regard to model-dependent lod-score analyses between atopic disorders and FCER1B, two-point analysis gave a lod score of z = 0.78 whereas two-locus analysis using a recessive-dominant mode of inheritance displayed a significant lod score of z = 3.55. Only 2 of 12 families showed evidence for linkage using the latter oligogenic model. In conclusion, the results of our study map the FCER1B gene in close proximity to D11S903, support the finding of Cookson et al. implicating the IgE high-affinity receptor gene (FCER1B) at 11q13, and furthermore suggest an oligogenic mode of inheritance as well as heterogeneity in the genetic susceptibility to atopy and atopic dermatitis. Received: 6 November 1995 / Accepted: 1 October 1997     

Hereditary neuralgic amyotrophy: evidence for genetic homogeneity and mapping to chromosome 17q25

Hereditary neuralgic amyotrophy (HNA) is a rare autosomal dominant disorder on chromosome 17q, associated with recurrent, episodic, painful brachial plexus neuropathy. Dysmorphic features, including hypotelorism, long nasal bridge and facial asymmetry, are frequently associated with HNA. To assess genetic homogeneity, determine the cytogenetic location, and identify flanking markers for the HNA locus, six pedigrees were studied with multiple DNA markers from distal chromosome 17q. The results in all pedigrees supported linkage of the HNA locus to chromosome 17. A maximum combined lod score (Ζ = 10.94, ￡ = 0.05) was obtained with marker D17S939 and the maximum multipoint lod score was 22.768 in the interval defined by D17S802– D17S939. An analysis of crossovers placed the HNA locus within an approximate 4.0-cM interval flanked by D17S1603 and D17S802. Analysis of DNA from a human/mouse somatic cell hybrid with linked markers suggests that band 17q25 harbors the HNA locus. These results support genetic homogeneity within HNA and define a specific interval and a precise cytogenetic location in chromosome 17q25 for this disorder. Received: 24 June 1997 / Accepted: 21 August 1997     

Assignment of human plasma methylumbelliferyl-tetra-N-acetylchitotetraoside hydrolase or chitinase to chromosome 1q by a linkage study

Plasma methylumbelliferyl tetra-N-acetylchitotetraoside hydrolase or chitinase (CHIT) might play a role in degrading the chitin wall of some microorganisms. In about 6% of Caucasian people the enzyme shows pseudodeficiency (defined as very low activity without apparent symptoms). We have mapped this locus by linkage analysis to the marker D1S306 (z = 4.00 at θ _{M = F} = 0.0) on chromosome 1q between the flanking markers D1S191 and D1S245 in the area of 1q31–1qter. Received: 13 December 1996 / Accepted: 8 July 1997     

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     

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     

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.     

A novel locus for autosomal dominant congenital motor nystagmus mapped to 1q31-q32.2 between D1S2816 and D1S2692

Congenital motor nystagmus (CMN) is characterized by bilateral involuntary ocular oscillation without any other underlying ocular or systemic diseases. An autosomal dominant CMN was identified in a large Chinese family where all patients had nystagmus since infancy. The nystagmus in the family is independent of any known ocular or systemic diseases. After exclusion of known CMN loci, a genome-wide scan was performed by genotyping microsatellite markers at about 10 cM intervals, together with two-point linkage analysis. Exome sequencing was used to screen coding exons of well-annotated genes. Sanger-dideoxy sequencing was used to verify candidate variations inside the linkage interval. Congenital motor nystagmus in this family shows linkage to markers in a 11.39 Mb (12.1 cM) region on chromosome 1q31-q32.2 between D1S2816 and D1S2692. All nine markers in the linkage interval gave positive lod scores, with D1S2655 and D1S2636 yielding lod scores of 5.16 and 5.18, respectively, at θ = 0. No causative mutation in the linkage interval was identified by exome sequencing of gDNA from four patients. A linkage study of additional families and further analysis of candidate genes may ultimately lead to identification of the gene responsible for dominantly inherited CMN.     

A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance.

Manic-depressive illness (MDI), also known as "bipolar affective disorder," is a common and devastating neuropsychiatric illness. Although pivotal biochemical alterations underlying the disease are unknown, results of family, twin, and adoption studies consistently implicate genetic transmission in the pathogenesis of MDI. In order to carry out linkage analysis, we ascertained eight moderately sized pedigrees containing multiple cases of the disease. For a four-allele marker mapping 5 cM from the disease gene, the pedigree sample has > 97% power to detect a dominant allele under genetic homogeneity and has > 73% power under 20% heterogeneity. To date, the eight pedigrees have been genotyped with 328 polymorphic DNA loci throughout the genome. When autosomal dominant inheritance was assumed, 273 DNA markers gave lod scores < -2.0 at recombination fraction (theta) = .0, 174 DNA loci produced lod scores < -2.0 at theta = .05, and 4 DNA marker loci yielded lod scores > 1 (chromosome 5--D5S39, D5S43, and D5S62; chromosome 11--D11S85). Of the markers giving lod scores > 1, only D5S62 continued to show evidence for linkage when the affected-pedigree-member method was used. The D5S62 locus maps to distal 5q, a region containing neurotransmitter-receptor genes for dopamine, norepinephrine, glutamate, and gamma-aminobutyric acid. Although additional work in this region may be warranted, our linkage results should be interpreted as preliminary data, as 68 unaffected individuals are not past the age of risk.     

Demonstration of a founder effect and fine mapping of dominant optic atrophy locus on 3q28-qter by linkage disequilibrium method

Dominant optic atrophy, a hereditary optic neuropathy causing decreased visual acuity, colour vision deficits, a centro-caecal scotoma and optic nerve pallor, has been mapped to a genetic interval of 1.4 cM between loci D3S3669 and D3S3562 on chromosome 3q28-qter. In order to further refine the critical disease interval, and to test the power of haplotype analysis and linkage disequilibrium mapping, we identified a total of 38 families with dominant optic atrophy, unrelated on the basis of genealogy, from a data base of genetic eye disease families originating from the British Isles. They were studied with 12 highly polymorphic microsatellite markers spanning a region of 12 cM around the dominant optic atrophy locus (OPA1). Allelic frequency analysis [chi-squared test, likeli-hood ratio test (LRT) and P values] and haplotype parsimony analysis showed evidence of a founder effect in 36 of the 38 pedigrees. Six markers (D3S3669, D3S1523, D3S3642, D3S2305, D3S3590 and D3S3562), spanning 1.4 cM across the disease-associated region, demonstrated significant linkage disequilibrium by LRT (P < 0.05). A peak LRT value of 10.86 (P < 0.0005, λ = 0.4) occurred at D3S3669. On linkage disequilibrium multipoint analysis the maximum lod score of 8.01 is achieved at D3S1523, and 95% confidence intervals suggest that OPA1 lies within ca. 400 kb of D3S1523. Received: 13 August 1997 / Accepted: 22 September 1997     

Connexin 50 mutation in a family with congenital "zonular nuclear" pulverulent cataract of Pakistani origin

Inherited cataract is a clinically and genetically heterogeneous disease that most often presents as a congenital autosomal dominant trait. Here we report linkage of a three-generation family of Pakistani origin with autosomal dominant cataract "zonular nuclear" pulverulent type (CZNP) on chromosome 1q21.1. Genome wide-linkage analysis excluded all the known cataract loci except on chromosome 1q. Significantly positive 2-point lod score values (Z=3.01 at θ=0) were obtained for markers D1S305 and D1S2721, which are known to flank the gene for connexin 50 (Cx50) or gap junction protein alpha-8 (Gja8). Previously a mutation in this gene has been reported in a British family with zonular pulverulent cataract (CZP).Here we describe a second mutation (E48K) in connexin 50 that confirms the involvement of this gene in cataractogenesis. Electronic Publication     

Localization of a novel locus for alopecia with mental retardation syndrome to chromosome 3q26.33–q27.3

Alopecia with mental retardation syndrome is a rare autosomal recessive disorder characterized clinically by total or partial alopecia and mental retardation. In an effort to understand the molecular bases of this form of alopecia syndrome, large Pakistani consanguineous kindred with multiple affected individuals has been ascertained from a remote region in Pakistan. Genome wide scan mapped the disease locus on chromosome 3q26.33–q27.3. A maximum two-point LOD score of 3.05 (θ=0.0) was obtained at marker D3S3583. Maximum multipoint LOD score exceeding 5.0, obtained with several markers, supported the linkage. Recombination events observed in affected individuals localized the disease locus between markers D3S1232 and D3S2436, spanning 11.49-cM region on chromosome 3q26.33–q27.3. Sequence analysis of a candidate gene ETS variant gene 5 from DNA samples of two affected individuals of the family revealed no mutation.     

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.     

Analysis of a second family with hereditary non-chromaffin paragangliomas locates the underlying gene at the proximal region of chromosome 11q

The gene for autosomal, dominantly inherited, non-chromaffin paragangliomas has previously been mapped at 11q23-qter by linkage analysis of a single family. In the present study, we have used genetic markers from 11q for the analysis of two distantly related pedigrees with the same disorder. Linkage analysis and haplotyping indicate that the gene underlying the disorder in the present family is located on chromosome 11q proximal to the tyrosinase gene locus (11q14–q21). Closely linked markers are the human homologue of the murine INT2 protooncogene and the anonymous DNA marker D11S527. A maximum lod score of 5.4 (=0.0) has been obtained for linkage between the disorder and the chromosomal region defined by these markers. The human INT2 gene can be regarded as a candidate for the disorder on the basis of its expression pattern during embryogenesis in the mouse. However, haplotype analysis indicates that this gene is probably not the predisposing genetic factor in the present family.     

Identification of genetic loci for basal cell nevus syndrome and inflammatory bowel disease in a single large pedigree

Basal Cell Nevus Syndrome (BCNS) is an autosomal dominant disease. PTCH1 gene mutations have been found responsible in many but not all pedigrees. Inflammatory Bowel Disease (IBD) is a complex genetic disorder, disproportionate in Ashkenazim, and characterized by chronic intestinal inflammation. We revisited a large Ashkenazim pedigree, first reported in 1968, with multiple diagnoses of BCNS and IBD, and with a common genetic cause for both disorders proposed. We expanded the pedigree to four generations and performed a genome-wide linkage study for BCNS and IBD traits. Twelve members with BCNS, seven with IBD, five with both diagnoses and eight unaffected were genotyped. Both non-parametric (GENEHUNTER 2.1) and parametric (FASTLINK) linkage analyses were performed and a validation through simulation was performed. BCNS linked to chromosome 9q22 (D9S1120) just proximal to the PTCH1 gene (NPL=3.26, P=0.003; parametric two-point LOD=2.4, parametric multipoint LOD=3.7). Novel IBD linkage evidence was observed at chromosome 1p13 (D1S420, NPL 3.92, P=0.0047; parametric two-point LOD=1.9). Linkage evidence was also observed to previously reported IBD loci on 4q, (D4S2623, NPL 3.02, P=0.012; parametric two-point LOD=2.15), 10q23 (D10S1225 near DLG5, NPL 3.33, P=0.0085; parametric two-point LOD=1.3), 12 overlapping the IBD2 locus (D12S313, NPL 2.6, P=0.018; parametric two-point LOD=1.52), and 7q (D7S510 and D7S3046, NPL 4.06, P=0.0035; parametric two-point LOD=2.18). In this pedigree affected by both BCNS and IBD, the two traits and their respective candidate genetic loci segregate independently; BCNS maps to the PTCH1 gene and IBD maps to several candidate regions, mostly overlapping previously observed IBD loci.Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.Carolien I. Panhuysen and Amir Karban contributed equally to this work     

Genetic linkage of progressive pseudorheumatoid dysplasia to a 3-cM interval of chromosome 6q22

Progressive pseudorheumatoid dysplasia (PPD), MIM 208230, is an autosomal-recessive disorder, clinically characterized by spondyloepiphyseal dysplasia and progressive arthropathy. Linkage analysis of three families of different geographic and ethnic origin, including 11 affected individuals, showed strong evidence for localization of a gene for progressive pseudorheumatoid dysplasia to chromosome 6q with a maximum two-point lod score for D6S1647 of 8.34 at θ=0. Analysis of regions of homozygosity placed the gene in a 3-cM interval between D6S1594 and D6S432. No significant shared haplotype was found for markers of the linked interval in the three families analyzed. Five genes encoding collagen and one encoding a specific procollagen-processing enzyme that map near this interval represent good candidates for the PPD gene. Received: 12 February 1998 / Accepted: 10 March 1998     

Genome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia

Multiple linkage regions have been reported in schizophrenia, and some appear to harbor susceptibility genes that are differentially expressed in postmortem brain tissue derived from unrelated individuals. We combined traditional genome-wide linkage analysis in a multiplex family with lymphocytic genome-wide expression analysis. A genome scan suggested linkage to a chromosome 4q marker (D4S1530, LOD 2.17, θ=0) using a dominant model. Haplotype analysis using flanking microsatellite markers delineated a 14 Mb region that cosegregated with all those affected. Subsequent genome-wide scan with SNP genotypes supported the evidence of linkage to 4q33–35.1 (LOD=2.39) using a dominant model. Genome-wide microarray analysis of five affected and five unaffected family members identified two differentially expressed genes within the haplotype AGA and GALNT7 (aspartylglucosaminidase and UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 7) with nominal significance; however, these genes did not remain significant following analysis of covariance. We carried out genome-wide linkage analyses between the quantitative expression phenotype and genetic markers. AGA expression levels showed suggestive linkage to multiple markers in the haplotype (maximum LOD=2.37) but to no other genomic region. GALNT7 expression levels showed linkage to regulatory loci at 4q28.1 (maximum LOD=3.15) and in the haplotype region at 4q33–35.1 (maximum LOD=2.37). ADH1B (alcohol dehydrogenase IB) was linked to loci at 4q21–q23 (maximum LOD=3.08) and haplotype region at 4q33–35.1 (maximum LOD=2.27). Seven differentially expressed genes were validated with RT-PCR. Three genes in the 4q33–35.1 haplotype region were also differentially expressed in schizophrenia in postmortem dorsolateral prefrontal cortex: AGA, HMGB2, and SCRG1. These results indicate that combining differential gene expression with linkage analysis may help in identifying candidate genes and potential regulatory sites. Moreover, they also replicate recent findings of complex trans- and cis- regulation of genes.     

The gene encoding human transmembrane secretory component (locus PIGR) is linked to D1S58 on chromosome 1

The human transmembrane secretory component (SC or poly-Ig receptor, PIGR) is expressed basolaterally on glandular epithelial cells and is responsible for the external translocation of polymeric IgA and IgM. SC is hence a key molecule in antibody protection of mucosal surfaces. The human SC gene (locus PIGR) is located on chromosome 1 (1q31–q41). Here we present the first genetic linkage study of PIGR versus syntenic markers, including D1S58 and F13B, which have been previously regionalized to 1q31–q32 and 1q31–q32.1, respectively. We found that PIGR is closely linked to D1S58 (lods + 5.06 at _max = 0.06, without sex difference). PIGR versus F13B showed + 1.46 at _max = 0.25 for both sexes combined. A recombination of 0.06 between F13B and D1S58 (lods + 2.24) was in contrast to a previously published study giving _max = 0.22 (lods + 3.9), the combined lods being 5.6 at _max = 0.20. The progeny of a triply heterozygotic female indicated that PIGR is the flanking locus, therefore suggesting a cen-F13B-D1S58-PIGR-qter gene sequence on human chromosome 1. Only negative lod scores to RH, C8@, and PGM1 on 1p, and FY on proximal 1q, were found. Current combined Norwegian allele frequencies were estimated for PIGR to be A1 = 0.63, A2 = 0.37 (370 chromosomes), and for D1S58 to be A1 = 0.44, A2 = 0.56 (218 chromosomes).     

Affected-sib-pair mapping of a novel susceptibility gene to insulin-dependent diabetes mellitus (IDDM8) on chromosome 6q25-q27.

Affected-sib-pair analyses were performed using 104 Caucasian families to map genes that predispose to insulin-dependent diabetes mellitus (IDDM). We have obtained linkage evidence for D6S446 (maximum lod score [MLS] = 2.8) and for D6S264 (MLS = 2.0) on 6q25-q27. Together with a previously reported data set, linkage can be firmly established (MLS = 3.4 for D6S264), and the disease locus has been designated IDDM8. With analysis of independent families, we confirmed linkage evidence for the previously identified IDDM3 (15q) and DDM7 (2q). We also typed additional markers in the regions containing IDDM3, IDDM4, IDDM5, and IDDM8. Preliminary linkage evidence for a novel region on chromosome 4q (D4S1566) has been found in 47 Florida families (P < .03). We also found evidence of linkage for two regions previously identified as potential linkages in the Florida subset: D3S1303 on 3q (P < .04) and D7S486 on 7q (P < .03). We could not confirm linkage with eight other regions (D1S191, D1S412, D4S1604, D8S264, D8S556, D10S193, D13S158, and D18S64) previously identified as potential linkages.     

A novel locus <Emphasis Type="Italic">DFNA59</Emphasis> for autosomal dominant nonsyndromic hearing loss maps at chromosome 11p14.2–q12.3

Autosomal dominant nonsyndromic hearing loss (ADNSHL) accounts for about one-fifth of hereditary hearing loss in humans. In the present study, we have analyzed a three-generation family with 14 of its members manifesting ADNSHL, using a genome-wide linkage mapping approach. We found a novel locus DFNA59 between the D11S929 and D11S480 markers in the chromosome location 11p14.2–q12.3. The highest two-point lod score of 5.72 at recombination fraction = 0 was obtained for D11S4152, D11S4154, D11S1301, D11S905 and D11S1344. The critical genomic region comprising about 37 megabases of DNA is proposed to carry a gene for ADNSHL in the family. About 50 cochlear-expressed genes mapping to the region are strong candidates which we propose to examine to identify the gene responsible for the hearing impairment. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Alignment of two genetic linkage maps on porcine chromosome 13

A set of four microsatellite markers from the USDA genetic linkage map of porcine chromosome 13 were mapped in the European Pig Gene Mapping Project (PiGMaP) reference pedigrees. A two-point linkage analysis was performed between these markers and a set of markers known to map to chromosome 13. Pairs of markers that had a lod score greater than three were used to construct a multi-point linkage map, permitting alignment of the United States Department of Agriculture (USDA) map to the PiGMaP.