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.     

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.     

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.     

Genetic Studies of Autistic Disorder and Chromosome 7

Genome-wide scans have suggested that a locus on 7q is involved in the etiology of autistic disorder (AD). We have identified an AD family in which three sibs inherited from their mother a paracentric inversion in the chromosome 7 candidate region (inv(7)(q22-q31.2)). Clinically, the two male sibs have AD, while the female sib has expressive language disorder. The mother carries the inversion, but does not express AD. Haplotype data on the family suggest that the chromosomal origin of the inversion was from the children's maternal grandfather. Based on these data, we have genotyped 76 multiplex (>/=2 AD affecteds/family) families for markers in this region of 7q. Two-point linkage analysis yielded a maximum heterogeneity lod score of 1.47 and maximum lod score (MLS) of 1.03 at D7S495. Multipoint MLS and NPL analyses resulted in peak scores of 1.77 at D7S2527 and 2.01 at D7S640. Examination of affected sibpairs revealed significant paternal (P = 0.007), but not maternal (P = 0. 75), identity-by-descent sharing at D7S640. Significant linkage disequilibrium was detected with paternal (P = 0.02), but not maternal (P = 0.15), transmissions at D7S1824 in multiplex and singleton families. There was also evidence for an increase in recombination in the region (D7S1817 to D7S1824) in the AD families versus non-AD families (P = 0.03, sex-averaged; and P = 0.01, sex-specific). These results provide further evidence for the presence of an AD locus on chromosome 7q, as well as provide evidence suggesting that this locus may be paternally expressed.     

Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24

Despite recent advances in the molecular genetics of type 2 diabetes, the majority of susceptibility genes in humans remain to be identified. We therefore conducted a 10-cM genomewide search (401 microsatellite markers) for type 2 diabetes-related traits in 637 members of 143 French pedigrees ascertained through multiple diabetic siblings, to map such genes in the white population. Nonparametric two-point and multipoint linkage analyzes-using the MAPMAKER-SIBS (MLS) and MAXIMUM-BINOMIAL-LIKELIHOOD (MLB) programs for autosomal markers and the ASPEX program for chromosome X markers-were performed with six diabetic phenotypes: diabetes and diabetes or glucose intolerance (GI), as well as with each of the two phenotypes associated with normal body weight (body-mass index<27 kg/m(2)) or early age at diagnosis (<45 years). In a second step, high-resolution genetic mapping ( approximately 2 cM) was performed in regions on chromosomes 1 and 3 loci showing the strongest linkage to diabetic traits. We found evidence for linkage with diabetes or GI diagnosed at age <45 years in 92 affected sib pairs from 55 families at the D3S1580 locus on chromosome 3q27-qter using MAPMAKER-SIBS (MLS = 4.67, P=.000004), supported by the MLB statistic (MLB-LOD=3.43, P=.00003). We also found suggestive linkage between the lean diabetic status and markers APOA2-D1S484 (MLS = 3. 04, P=.00018; MLB-LOD=2.99, P=.00010) on chromosome 1q21-q24. Several other chromosomal regions showed indication of linkage with diabetic traits, including markers on chromosome 2p21-p16, 10q26, 20p, and 20q. These results (a) showed evidence for a novel susceptibility locus for type 2 diabetes in French whites on chromosome 3q27-qter and (b) confirmed the previously reported diabetes-susceptibility locus on chromosome 1q21-q24. Saturation on both chromosomes narrowed the regions of interest down to an interval of <7 cM.     

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 locus heterogeneity in human autosomal dominant split hand/split foot malformation.

Split hand/split foot (SHSF; also known as ectrodactyly) is a human developmental disorder characterized by missing central digits and other distal limb malformations. An association between SHSF and cytogenetically visible rearrangements of chromosome 7 at bands q21-q22 provides compelling evidence for the location of a causative gene at this location, and the locus has been designated SHFD1. In the present study, marker loci were localized to the SHFD1 critical region through the analysis of somatic cell hybrids derived from individuals with SHSF and cytogenetic abnormalities involving the 7q21-q22 region. Combined genetic and physical data suggest that the order of markers in the SHFD1 critical region is cen-D7S492-D7S527-(D7S479-D7S491)-SHFD1-++ +D7S554-D7S518-qter. Dinucleotide repeat polymorphisms at three of these loci were used to test for linkage of SHSF to this region in a large pedigree that demonstrates autosomal dominant SHSF. Evidence against linkage of the SHSF gene to 7q21-q22 was obtained in this pedigree. Therefore, combined molecular and genetic data provide evidence for locus heterogeneity in autosomal dominant SHSF. We propose the name SHSF2 for this second locus.     

A novel linkage to generalized vitiligo on 4q13-q21 identified in a genomewide linkage analysis of Chinese families

Generalized vitiligo is a common, autoimmune, familial-clustering depigmentary disorder of the skin and hair that results from selective destruction of melanocytes. Generalized vitiligo is likely a heterogeneous disease, with five susceptibility loci reported so far--on chromosomes 1p31, 6p21, 7q, 8p, and 17p13--in white populations. To investigate vitiligo susceptibility loci in the Chinese population, we performed a genomewide linkage analysis in 57 multiplex Chinese families, each with at least two affected siblings, and we identified interesting linkage evidence on 1p36, 4q13-q21, 6p21-p22, 6q24-q25, 14q12-q13, and 22q12. Subsequently, to extract more linkage information, we investigated our initial genomewide linkage findings in a follow-up analysis of 49 new families and additional markers. Our initial genomewide linkage analysis and our subsequent follow-up analysis have identified a novel linkage to vitiligo on 4q13-q21, with highly significant linkage evidence (a nonparametic LOD score of 4.62 [P=.000003] and a heterogeneity LOD score of 4.01, under a recessive inheritance model), suggesting that 4q13-q21 likely harbors a major susceptibility locus for vitiligo in the Chinese population. We observed a minimal overlap between the linkage results of our current genomewide analysis in the Chinese population and the results of previous analyses in white populations, and we thus hypothesize that, as a polygenic disorder, vitiligo may be associated with great genetic heterogeneity and a substantial difference in its genetic basis between ethnic populations.     

The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder: strong evidence of epistatic effects between loci on chromosomes 2q and 6q

We present the first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder (BPAD), using a large linkage data set (52 families of European descent; 448 participants and 259 affected individuals). Our results provide the strongest interaction evidence between BPAD genes on chromosomes 2q22-q24 and 6q23-q24, which was observed symmetrically in both directions (nonparametric LOD [NPL] scores of 7.55 on 2q and 7.63 on 6q; P<.0001 and P=.0001, respectively, after a genomewide permutation procedure). The second-best BPAD interaction evidence was observed between chromosomes 2q22-q24 and 15q26. Here, we also observed a symmetrical interaction (NPL scores of 6.26 on 2q and 4.59 on 15q; P=.0057 and .0022, respectively). We covered the implicated regions by genotyping additional marker sets and performed a detailed interaction linkage analysis, which narrowed the susceptibility intervals. Although the heterogeneity analysis produced less impressive results (highest NPL score of 3.32) and a less consistent picture, we achieved evidence of locus heterogeneity at chromosomes 2q, 6p, 11p, 13q, and 22q, which was supported by adjacent markers within each region and by previously reported BPAD linkage findings. Our results provide systematic insights in the framework of BPAD epistasis and locus heterogeneity, which should facilitate gene identification by the use of more-comprehensive cloning strategies.     

Dense‐map genome scan for dyslexia supports loci at 4q13, 16p12, 17q22; suggests novel locus at 7q36

Analysis of genetic linkage to dyslexia was performed using 133,165 array‐based SNPs genotyped in 718 persons from 101 dyslexia‐affected families. Results showed five linkage peaks with lod scores >2.3 (4q13.1, 7q36.1‐q36.2, 7q36.3, 16p12.1, and 17q22). Of these five regions, three have been previously implicated in dyslexia (4q13.1, 16p12.1, and 17q22), three have been implicated in attention‐deficit hyperactivity disorder (ADHD, which highly co‐occurs with dyslexia; 4q13.1, 7q36.3, 16p12.1) and four have been implicated in autism (a condition characterized by language deficits; 7q36.1‐q36.2, 7q36.3, 16p12.1, and 17q22). These results highlight the reproducibility of dyslexia linkage signals, even without formally significant lod scores, and suggest dyslexia predisposing genes with relatively major effects and locus heterogeneity. The largest lod score (2.80) occurred at 17q22 within the MSI2 gene, involved in neuronal stem cell lineage proliferation. Interestingly, the 4q13.1 linkage peak (lod 2.34) occurred immediately upstream of the LPHN3 gene, recently reported both linked and associated with ADHD. Separate analyses of larger pedigrees revealed lods >2.3 at 1–3 regions per family; one family showed strong linkage (lod 2.9) to a known dyslexia locus (18p11) not detected in our overall data, demonstrating the value of analyzing single large pedigrees. Association analysis identified no SNPs with genome‐wide significance, although a borderline significant SNP (P = 6 × 10^–7) occurred at 5q35.1 near FGF18, involved in laminar positioning of cortical neurons during development. We conclude that dyslexia genes with relatively major effects exist, are detectable by linkage analysis despite genetic heterogeneity, and show substantial overlapping predisposition with ADHD and autism.     

Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11

We completed fine mapping of nine positional candidate regions for attention-deficit/hyperactivity disorder (ADHD) in an extended population sample of 308 affected sibling pairs (ASPs), constituting the largest linkage sample of families with ADHD published to date. The candidate chromosomal regions were selected from all three published genomewide scans for ADHD, and fine mapping was done to comprehensively validate these positional candidate regions in our sample. Multipoint maximum LOD score (MLS) analysis yielded significant evidence of linkage on 6q12 (MLS 3.30; empiric P=.024) and 17p11 (MLS 3.63; empiric P=.015), as well as suggestive evidence on 5p13 (MLS 2.55; empiric P=.091). In conjunction with the previously reported significant linkage on the basis of fine mapping 16p13 in the same sample as this report, the analyses presented here indicate that four chromosomal regions--5p13, 6q12, 16p13, and 17p11--are likely to harbor susceptibility genes for ADHD. The refinement of linkage within each of these regions lays the foundation for subsequent investigations using association methods to detect risk genes of moderate effect size.     

Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III

Schizophrenia candidate regions 33-51 cM in length on chromosomes 5q, 6q, 10p, and 13q were investigated for genetic linkage with mapped markers with an average spacing of 5.64 cM. We studied 734 informative multiplex pedigrees (824 independent affected sibling pairs [ASPs], or 1,003 ASPs when all possible pairs are counted), which were collected in eight centers. Cases with diagnoses of schizophrenia or schizoaffective disorder (DSM-IIIR criteria) were considered affected (n=1,937). Data were analyzed with multipoint methods, including nonparametric linkage (NPL), ASP analysis using the possible-triangle method, and logistic-regression analysis of identity-by-descent (IBD) sharing in ASPs with sample as a covariate, in a test for intersample heterogeneity and for linkage with allowance for intersample heterogeneity. The data most supportive for linkage to schizophrenia were from chromosome 6q; logistic-regression analysis of linkage allowing for intersample heterogeneity produced an empirical P value <.0002 with, or P=.0004 without, inclusion of the sample that produced the first positive report in this region; the maximum NPL score in this region was 2.47 (P=.0046), the maximum LOD score (MLS) from ASP analysis was 3.10 (empirical P=.0036), and there was significant evidence for intersample heterogeneity (empirical P=.0038). More-modest support for linkage was observed for chromosome 10p, with logistic-regression analysis of linkage producing an empirical P=. 045 and with significant evidence for intersample heterogeneity (empirical P=.0096).     

Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26

Endometriosis is a common gynecological disease that affects up to 10% of women in their reproductive years. It causes pelvic pain, severe dysmenorrhea, and subfertility. The disease is defined as the presence of tissue resembling endometrium in sites outside the uterus. Its cause remains uncertain despite >50 years of hypothesis-driven research, and thus the therapeutic options are limited. Disease predisposition is inherited as a complex genetic trait, which provides an alternative route to understanding the disease. We seek to identify susceptibility loci, using a positional-cloning approach that starts with linkage analysis to identify genomic regions likely to harbor these genes. We conducted a linkage study of 1,176 families (931 from an Australian group and 245 from a U.K. group), each with at least two members--mainly affected sister pairs--with surgically diagnosed disease. We have identified a region of significant linkage on chromosome 10q26 (maximum LOD score [MLS] of 3.09; genomewide P = .047) and another region of suggestive linkage on chromosome 20p13 (MLS = 2.09). Minor peaks (with MLS > 1.0) were found on chromosomes 2, 6, 7, 8, 12, 14, 15, and 17. This is the first report of linkage to a major locus for endometriosis. The findings will facilitate discovery of novel positional genetic variants that influence the risk of developing this debilitating disease. Greater understanding of the aberrant cellular and molecular mechanisms involved in the etiology and pathophysiology of endometriosis should lead to better diagnostic methods and targeted treatments.     

Localization of one gene for tuberous sclerosis within 9q32-9q34, and further evidence for heterogeneity.

Tuberous sclerosis (TSC) is an autosomal dominant disorder with both neurological and cutaneous manifestations often resulting in significant disability. Although it has been studied clinically and biochemically for many years, the underlying pathophysiology remains unknown. Genetic linkage analysis provides an alternative strategy for understanding the genetic etiology of this disease. Genetic linkage of a gene for TSC to loci in 9q32-9q34 has been reported but has not been a universal finding, since absence of linkage to 9q loci, as well as linkage to loci on 11q, have also been reported. We present here data on 22 families (21 previously unreported) segregating TSC. Our results strongly support a TSC locus in the 9q32-34 region for approximately one-third of families and provide significant evidence for genetic heterogeneity. Application of newly described highly polymorphic dinucleotide repeat marker loci in TSC greatly enhanced the informativeness of our pedigrees and was vital for detecting the heterogeneity. No clear evidence of linkage to chromosome 11q22 markers was found, suggesting that a still unidentified TSC locus elsewhere in the genome may account for the majority of TSC families.     

Localization and replication of the systemic lupus erythematosus linkage signal at 4p16: interaction with 2p11, 12q24 and 19q13 in European Americans

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by both population and phenotypic heterogeneity. Our group previously identified linkage to SLE at 4p16 in European Americans (EA). In the present study we replicate this linkage effect in a new cohort of 76 EA families multiplex for SLE by model-free linkage analysis. Using densely spaced microsatellite markers in the linkage region, we have localized the potential SLE susceptibility gene(s) to be telomeric to the marker D4S2928 by haplotype construction. In addition, marker D4S394 showed marginal evidence of linkage disequilibrium with the putative disease locus by the transmission disequilibrium test and significant evidence of association using a family-based association approach as implemented in the program ASSOC. We also performed both two-point and multipoint model-based analyses to characterize the genetic model of the potential SLE susceptibility gene(s), and the lod scores both maximized under a recessive model with penetrances of 0.8. Finally, we performed a genome-wide scan of the total 153 EA pedigrees and evaluated the possibility of interaction between linkage signals at 4p16 and other regions in the genome. Fourteen regions on 11 chromosomes (1q24, 1q42, 2p11, 2q32, 3p14.2, 4p16, 5p15, 7p21, 8p22, 10q22, 12p11, 12q24, 14q12, 19q13) showed evidence of linkage, among which, signals at 2p11, 12q24 and 19q13 also showed evidence of interaction with that at 4p16. These results provide important additional information about the SLE linkage effect at 4p16 and offer a unique approach to uncovering susceptibility loci involved in complex human diseases.     

Subsets of Finns with high HDL to total cholesterol ratio show evidence for linkage to type 2 diabetes on chromosome 6q

OBJECTIVES: The purpose of this study was to examine carefully heterogeneity underlying evidence for linkage to type 2 diabetes (T2DM) on chromosome 6q from two sets of FUSION families. METHODS: Ordered subsets analysis (OSA) was performed on two sets of FUSION families. For OSA results showing significant improvement in evidence for linkage, T2DM-related phenotypes were compared between individuals with T2DM within the subset versus the complement. RESULTS: OSA analysis revealed 105 families with the highest average HDL to total cholesterol ratio (HDL ratio) that had strongly increased evidence for linkage (MLS = 7.91 at 78.0 cM; uncorrected p = 0.00002). Subjects with T2DM within this subset were significantly leaner, had lower fasting glucose, insulin, and C-peptide, and more favorable cardiovascular risk profile compared to the complement set of subjects with T2DM. OSA also revealed 33 families with the lowest average fasting insulin that had increased evidence for linkage at a second locus (MLS = 3.45 at 128 cM; uncorrected p = 0.017) coincident with quantitative trait locus linkage analysis results for fasting and 2-hour insulin in subjects without T2DM. CONCLUSIONS: These results suggest two diabetes susceptibility loci on chromosome 6q that may affect subsets of individuals with a milder form of T2DM.     

Genetic heterogeneity in Italian families with IgA nephropathy: suggestive linkage for two novel IgA nephropathy loci

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, but its etiologic mechanisms are still poorly understood. Different prevalences among ethnic groups and familial aggregation, together with an increased familial risk, suggest important genetic influences on its pathogenesis. A locus for familial IgAN, called "IGAN1," on chromosome 6q22-23 has been described, without the identification of any responsible gene. The partners of the European IgAN Consortium organized a second genomewide scan in 22 new informative Italian multiplex families. A total of 186 subjects (59 affected and 127 unaffected) were genotyped and were included in a two-stage genomewide linkage analysis. The regions 4q26-31 and 17q12-22 exhibited the strongest evidence of linkage by nonparametric analysis (best P=.0025 and .0045, respectively). These localizations were also supported by multipoint parametric analysis, in which peak LOD scores of 1.83 ( alpha =0.50) and 2.56 ( alpha =0.65) were obtained using the affected-only dominant model, and by allowance for the presence of genetic heterogeneity. Our results provide further evidence for genetic heterogeneity among families with IgAN. Evidence of linkage to multiple chromosomal regions is consistent with both an oligo/polygenic and a multiple-susceptibility-gene model for familial IgAN, with small or moderate effects in determining the pathological phenotype. Although we identified new candidate regions, replication studies are required to confirm the genetic contribution to familial IgAN.     

The genetics of reading disability in an often excluded sample: novel loci suggested for reading disability in rolandic epilepsy

Background

Reading disability (RD) is a common neurodevelopmental disorder with genetic basis established in families segregating “pure” dyslexia. RD commonly occurs in neurodevelopmental disorders including Rolandic Epilepsy (RE), a complex genetic disorder. We performed genomewide linkage analysis of RD in RE families, testing the hypotheses that RD in RE families is genetically heterogenenous to pure dyslexia, and shares genetic influences with other sub-phenotypes of RE.

Methods

We initially performed genome-wide linkage analysis using 1000 STR markers in 38 US families ascertained through a RE proband; most of these families were multiplex for RD. We analyzed the data by two-point and multipoint parametric LOD score methods. We then confirmed the linkage evidence in a second US dataset of 20 RE families. We also resequenced the SEMA3C gene at the 7q21 linkage locus in members of one multiplex RE/RD pedigree and the DISC1 gene in affected pedigrees at the 1q42 locus.

Results

In the discovery dataset there was suggestive evidence of linkage for RD to chromosome 7q21 (two-point LOD score 3.05, multipoint LOD 3.08) and at 1q42 (two-point LOD 2.87, multipoint LOD 3.03). Much of the linkage evidence at 7q21 derived from families of French-Canadian origin, whereas the linkage evidence at 1q42 was well distributed across all the families. There was little evidence for linkage at known dyslexia loci. Combining the discovery and confirmation datasets increased the evidence at 1q42 (two-point LOD = 3.49, multipoint HLOD = 4.70), but decreased evidence at 7q21 (two-point LOD = 2.28, multipoint HLOD  = 1.81), possibly because the replication sample did not have French Canadian representation.

Discussion

Reading disability in rolandic epilepsy has a genetic basis and may be influenced by loci at 1q42 and, in some populations, at 7q21; there is little evidence of a role for known DYX loci discovered in “pure” dyslexia pedigrees. 1q42 and 7q21 are candidate novel dyslexia loci.     

Identification of susceptibility loci for nonsyndromic cleft lip with or without cleft palate in a two stage genome scan of affected sib-pairs

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a complex disorder of multigenic origin involving between two and ten loci. Linkage and association studies of CL/P have implicated a number of candidate genes and regions but have often proved difficult to replicate. Here, we report the findings from a two-stage genome-wide scan of 92 affected sib-pairs to identify susceptibility loci to CL/P. An initial set of 400 microsatellite markers was used, with an average spacing of 10 cM throughout the genome. Eleven regions on eight chromosomes were found to have a P-value smaller than 0.05. These eight chromosomes were then further mapped with a second set of markers to increase the average map density to 5 cM. In seven out of eleven areas densely mapped, significance was markedly increased by decreasing the marker interval. Excessive allele sharing was found at 1p (NPL=2.35, P=0.009, MLS=1.51), 2p (NPL=1.77, P= 0.04, MLS=0.66), 6p (NPL=2.35, P=0.009, MLS=1.34), 8q (NPL=2.15, P=0.015, MLS= 1.51) 11 cen (NPL=2.70, P=0.003, MLS=2.10), 12q (NPL=2.08, P=0.02, MLS= 1.5), 16p (NPL=2.1, P=0.018, MLS=0.97) and Xcen-q (NPL=2.40, P=0.008, MLS=2.68). Although none reached the level required for significant susceptibility loci, two of these areas have previously been implicated in CL/P, viz. 2p13, an area harbouring the TGFA gene, and 6p23-24. We also demonstrate highly suggestive linkage to a susceptibility locus for nonsyndromic clefting on the X chromosome. Further studies are currently underway to replicate these findings in a larger cohort of affected sib-pairs.     

Major genes regulating total serum immunoglobulin E levels in families with asthma

Immunoglobulin E (IgE) has a major role in the pathogenesis of allergic disorders and asthma. Previous data from 92 families, each identified through a proband with asthma, showed evidence for two major genes regulating total serum IgE levels. One of these genes mapped to 5q31-33. In the current study, the segregation analysis was extended by the addition of 108 probands and their families, ascertained in the same manner. A mixed recessive model (i.e., major recessive gene and residual genetic effect) was the best-fitting and most-parsimonious one-locus model of the segregation analysis. A mixed two-major-gene model (i.e., two major genes and residual genetic effect) fit the data significantly better than did the mixed recessive one-major-gene model. The second gene modified the effect of the first recessive gene. Individuals with the genotype aaBB (homozygous high-risk allele at the first gene and homozygous low-risk allele at the second locus) had normal IgE levels (mean 23 IU/ml), and only individuals with genotypes aaBb and aabb had high IgE levels (mean 282 IU/ml). A genomewide screening was performed using variance-component analysis. Significant evidence for linkage was found for a novel locus at 7q, with a multipoint LOD score of 3. 36 (P=.00004). A LOD score of 3.65 (P=.00002) was obtained after genotyping additional markers in this region. Evidence for linkage was also found for two previously reported regions, 5q and 12q, with LOD scores of 2.73 (P=.0002) and 2.46 (P=.0004), respectively. These results suggest that several major genes, plus residual genetic effects, regulate total serum IgE levels.