Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11

Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is the most common behavioral disorder of childhood. Twin, adoption, segregation, association, and linkage studies have confirmed that genetics plays a major role in conferring susceptibility to ADHD. We applied model-based and model-free linkage analyses, as well as the pedigree disequilibrium test, to the results of a genomewide scan of extended and multigenerational families with ADHD from a genetic isolate. In these families, ADHD is highly comorbid with conduct and oppositional defiant disorders, as well as with alcohol and tobacco dependence. We found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11 in individual families. Fine mapping applied to these regions resulted in significant linkage in the combined families at chromosomes 4q13.2 (two-point allele-sharing LOD score from LODPAL = 4.44 at D4S3248), 5q33.3 (two-point allele-sharing LOD score from LODPAL = 8.22 at D5S490), 11q22 (two-point allele-sharing LOD score from LODPAL = 5.77 at D11S1998; multipoint nonparametric linkage [NPL]-log[P value] = 5.49 at approximately 128 cM), and 17p11 (multipoint NPL-log [P value] >12 at approximately 12 cM; multipoint maximum location score 2.48 [alpha = 0.10] at approximately 12 cM; two-point allele-sharing LOD score from LODPAL = 3.73 at D17S1159). Additionally, suggestive linkage was found at chromosome 8q11.23 (combined two-point NPL-log [P value] >3.0 at D8S2332). Several of these regions are novel (4q13.2, 5q33.3, and 8q11.23), whereas others replicate already-published loci (11q22 and 17p11). The concordance between results from different analytical methods of linkage and the replication of data between two independent studies suggest that these loci truly harbor ADHD susceptibility genes.     

Multilocus and interaction-based genome scan for alcoholism risk factors in Caucasian Americans: the COGA study

In this paper, we applied the nonparametric linkage regression approach to the Caucasian genome scan data from the Collaborative Study on the Genetics of Alcoholism to search for regions of the genome that exhibit evidence for linkage to putative alcoholism-predisposing genes. The multipoint single-locus model identified four regions of the genome with LOD scores greater than one. These regions were on 7p near D7S1790 (LOD = 1.31), two regions on 7q near D7S1870 (LOD = 1.15) and D7S1799 (LOD = 1.13) and 21q near D21S1440 and D21S1446 (LOD = 1.78). Jointly modeling these loci provided stronger evidence for linkage in each of these regions (LOD = 1.58 on 7q11, LOD = 1.61 on 11q23, and LOD = 1.95 on 21q22). The evidence for linkage tended to increase among pedigrees with earlier mean age of onset at 8q23 (p = 0.0016), 14q21 (p = 0.0079), and 18p12 (p = 0.0021) and with later mean age of onset at 4q35 (p = 0.0067) and 9p22 (p = 0.0008).     

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     

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.     

Age-related macular degeneration--a genome scan in extended families

We performed a genomewide scan and genetic linkage analysis, to identify loci associated with age-related macular degeneration (AMD). We collected 70 families, ranging from small nuclear families to extended multigenerational pedigrees and consisting of a total of 344 affected and 217 unaffected members available for genotyping. We performed linkage analyses using parametric and allele-sharing models. We performed the analyses on the complete pedigrees but also subdivided the families into nuclear pedigrees. Finally, to dissect potential genetic factors responsible for differences in disease manifestation, we stratified the sample by two major AMD phenotypes (neovascular AMD and geographic atrophy) and by age of affected family members at the time of our evaluation. We have previously demonstrated linkage between AMD and 1q25-31 in a single large family. In the combined sample, we have detected the following loci with scores exceeding a LOD=2 cutoff under at least one of the models considered: 1q31 (HLOD=2.07 at D1S518), 3p13 (HLOD=2.19 at D3S1304/D3S4545), 4q32 (HLOD=2.66 at D4S2368, for the subset of families with predominantly dry AMD), 9q33 (LODZlr=2.01 at D9S930/D9S934), and 10q26 (HLOD=3.06 at D10S1230). Using correlation analysis, we have found a statistically significant correlation between LOD scores at 3p13 and 10q26, providing evidence for epistatic interactions between the loci and, hence, a complex basis of AMD. Our study has identified new loci that should be considered in future mapping and mutational analyses of AMD and has strengthened the evidence in support of loci suggested by other studies.     

Genetic determination of osteoporosis: lessons learned from a large genome-wide linkage study

Osteoporosis is a common disease with strong genetic control. We performed an autosomal linkage scan in a large pedigree-based sample of 4,498 subjects for a composite osteoporosis phenotype that combines osteoporotic fracture (OF) and low bone mineral density (BMD). All of the subjects were U.S. Caucasians recruited in the Omaha area of Nebraska. Sex-specific linkage analyses and autosomal imprinting analyses were also conducted. For conventional linkage analyses in the total sample, we identified suggestive linkage on chromosomes 14q32 (LOD = 2.61), 7p14 (LOD = 2.42), and 11q25 (LOD = 2.09). In female subjects a significant linkage signal was detected on chromosome 14q22 (LOD = 3.53) and another two peaks were detected on chromosomes 7p14 (LOD = 3.07) and 9p21 (LOD = 2.29). Suggestive evidence of imprinted loci was found with paternally derived alleles on chromosomes 1q42 (LOD = 2.12) and 9q34 (LOD = 1.88). Some evidence of linkage to maternally derived alleles was found on chromosome 7q22 (LOD = 1.67). Our study provides new clues to osteoporosis genetic research and for the first time suggests that genomic imprinting effects may play a role in the etiology of osteoporosis.     

A genome scan for serum triglyceride in obese nuclear families

Serum triglyceride (TG) levels are increased in extremely obese individuals, indicating abnormalities in lipid metabolism and insulin resistance. We carried out a genome scan for serum TG in 320 nuclear families segregating extreme obesity and normal weight. Three hundred eighty-two Marshfield microsatellite markers (Screening Set 11) were genotyped. Quantitative linkage analyses were performed using family regression and variance components methods. We found linkage on the 7q36 region [D7S3058, 174 centimorgan (cM), Logarithm of Odds (LOD) = 2.98] for log-transformed TG. We also found suggestive linkages on chromosomes 20 (D20S164, 101 cM, LOD = 2.34), 13 (111 cM, LOD = 2.00), and 9 (104 cM, LOD = 1.90) as well as some weaker trends for chromosomes 1, 3, 5, 10, 12, and 22. In 58 African American families, LOD scores of 3.66 and 2.62 were observed on two loci on chromosome 16: D16S3369 (64 cM) and MFD466 (100 cM). To verify the 7q36 linkage, we added 60 nuclear families, and the LOD score increased to 3.52 (empirical P < 0.002) on marker D7S3058.     

Genome-wide linkage scan reveals multiple susceptibility loci influencing lipid and lipoprotein levels in the Quebec Family Study

A genome-wide linkage study was performed to identify chromosomal regions harboring genes influencing lipid and lipoprotein levels. Linkage analyses were conducted for four quantitative lipoprotein/lipid traits, i.e., total cholesterol, triglyceride, HDL-cholesterol (HDL-C), and LDL-C concentrations, in 930 subjects enrolled in the Québec Family Study. A maximum of 534 pairs of siblings from 292 nuclear families were available. Linkage was tested using both allele-sharing and variance-component linkage methods. The strongest evidence of linkage was found on chromosome 12q14.1 at marker D12S334 for HDL-C, with a logarithm of the odds (LOD) score of 4.06. Chromosomal regions harboring quantitative trait loci (QTLs) for LDL-C included 1q43 (LOD = 2.50), 11q23.2 (LOD = 3.22), 15q26.1 (LOD = 3.11), and 19q13.32 (LOD = 3.59). In the case of triglycerides, three markers located on 2p14, 11p13, and 11q24.1 provided suggestive evidence of linkage (LOD > 1.75). Tests for total cholesterol levels yielded significant evidence of linkage at 15q26.1 and 18q22.3 with the allele-sharing linkage method, but the results were nonsignificant with the variance-component method. In conclusion, this genome scan provides evidence for several QTLs influencing lipid and lipoprotein levels. Promising candidate genes were located in the vicinity of the genomic regions showing evidence of linkage.     

Linkage analysis of familial Alzheimer disease, using chromosome 21 markers

Chromosome 21 markers were tested for linkage to familial Alzheimer disease (FAD) in 48 kindreds. These families had multiple cases of Alzheimer disease (AD) in 2 or more generations with family age-at-onset means (M) ranging from 41 to 83 years. Included in this group are seven Volga German families which are thought to be genetically homogeneous with respect to FAD. Autopsy documentation of AD was available for 32 families. Linkage to the 21 q11-q21 region was tested using D21S16, D21S13, D21S110, D21S1/S11, and the APP gene as genetic markers. When linkage results for all the families were summed, the LOD scores for these markers were consistently negative and the entire region was formally excluded. Linkage results were also summed for the following family groups; late-onset (M greater than 60), early-onset (M less than or equal to 60), Volga Germans (M = 56), and early-onset non-Volga Germans (M less than or equal to 60). For the first three groups, LOD scores were negative for this region. For the early-onset non-Volga German group (six families), small positive LOD scores of Zmax = 0.78 (recombination fraction theta = .15), Zmax = 0.27 (theta = .15), and Zmax = 0.64 (theta = .0), were observed for D21S13, D21S16, and D21S110, respectively. The remainder of the long arm of chromosome 21 was tested for linkage to FAD using seven markers spanning the q22 region. Results for these markers were also predominantly negative. Thus it is highly unlikely that a chromosome 21 gene is responsible for late-onset FAD and at least some forms of early-onset FAD represented by the Volga German kindreds.     

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.     

A Genome‐Wide Scan for Body Mass Index among Nigerian Families

Objective: Interest in mapping genetic variants that are associated with obesity remains high because of the increasing prevalence of obesity and its complications worldwide. Data on genetic determinants of obesity in African populations are rare. Research Methods and Procedures: We have undertaken a genome‐wide scan for body mass index (BMI) in 182 Nigerian families that included 769 individuals. Results: The prevalence of obesity was only 5%, yet polygenic heritability for BMI was in the expected range (0.46 ± 0.07). Tandem repeat markers (402) were typed across the genome with an average map density of 9 cM. Pedigree‐based analysis using a variance components linkage model demonstrated evidence for linkage on chromosome 7 (near marker D7S817 at 7p14) with a logarithm of odds (LOD) score of 3.8 and on chromosome 11 (marker D11S2000 at 11q22) with an LOD score of 3.3. Weaker evidence for linkage was found on chromosomes 1 (1q21, LOD = 2.2) and 8 (8p22, LOD = 2.3). Several candidate genes, including neuropeptide Y, DRD2, APOA4, lamin A/C, and lipoprotein lipase, lie in or close to the chromosomal regions where strong linkage signals were found. Discussion: The findings of this study suggest that, as in other populations with higher prevalences of obesity, positive linkage signals can be found on genome scans for obesity‐related traits. Follow‐up studies may be warranted to investigate these linkages, especially the one on chromosome 11, which has been reported in a population at the opposite end of the BMI distribution.     

Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative

We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites. A 9-cM screen was performed by use of 391 markers, with an average heterozygosity of 0.76. Multipoint, nonparametric linkage analyses were conducted in affected relative pairs. Additionally, simulation analyses were performed to determine genomewide significance levels for this study. Three hierarchical models of affection were analyzed. Significant evidence for linkage (genomewide P<.05) was found on chromosome 17q, with a peak maximum LOD score of 3.63, at the marker D17S928, and on chromosome 6q, with a peak maximum LOD score of 3.61, near the marker D6S1021. These loci met both standard and simulation-based criteria for genomewide significance. Suggestive evidence of linkage was observed in three other regions (genomewide P<.10), on chromosomes 2p, 3q, and 8q. This study, which is based on the largest linkage sample for bipolar disorder analyzed to date, indicates that several genes contribute to bipolar disorder.     

Fine mapping of the nail-patella syndrome locus at 9q34.

Nail-patella syndrome (NPS), or onychoosteodysplasia, is an autosomal dominant, pleiotropic disorder characterized by nail dysplasia, absent or hypoplastic patellae, iliac horns, and nephropathy. Previous studies have demonstrated linkage of the nail-patella locus to the ABO and adenylate kinase loci on human chromosome 9q34. As a first step toward isolating the NPS gene, we present linkage analysis with 13 polymorphic markers in five families with a total of 69 affected persons. Two-point linkage analysis with the program MLINK showed tight linkage of NPS and the anonymous markers D9S112 (LOD = 27.0; theta = .00) and D9S315 (LOD = 22.0; theta = .00). Informative recombination events place the NPS locus within a 1-2-cM interval between D9S60 and the adenylate kinase gene (AK1).     

Genome screening in human systemic lupus erythematosus: results from a second Minnesota cohort and combined analyses of 187 sib-pair families

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a loss of immunologic tolerance to a multitude of self-antigens. Epidemiological data suggest an important role for genes in the etiology of lupus, and previous genetic studies have implicated the HLA locus, complement genes, and low-affinity IgG (Fcgamma) receptors in SLE pathogenesis. In an effort to identify new susceptibility loci for SLE, we recently reported the results of a genomewide microsatellite marker screen in 105 SLE sib-pair families. By using nonparametric methods, evidence for linkage was found in four intervals: 6p11-21 (near the HLA), 16q13, 14q21-23, and 20p12.3 (LOD scores >/=2.0), and weaker evidence in another nine regions. We now report the results of a second complete genome screen in a new cohort of 82 SLE sib-pair families. In the cohort 2 screen, the four best intervals were 7p22 (LOD score 2.87), 7q21 (LOD score 2.40), 10p13 (LOD score 2.24), and 7q36 (LOD score 2.15). Eight additional intervals were identified with LOD scores in the range 1.00-1.67. A combined analysis of MN cohorts 1 and 2 (187 sib-pair families) showed that markers in 6p11-p21 (D6S426, LOD score 4.19) and 16q13 (D16S415, LOD score 3.85) met the criteria for significant linkage. Three intervals (2p15, 7q36, and 1q42) had LOD scores in the range 1.92-2.06, and another 13 intervals had LOD scores in the range of 1.00-1.78 in the combined sample. These data, together with other available gene mapping results in SLE, are beginning to allow a prioritization of genomic intervals for gene discovery efforts in human SLE.     

Linkage analysis of the human dopamine beta-hydroxylase gene

The human gene for dopamine beta-hydroxylase (D beta H) has been mapped to chromosome 9q34. Using polymerase chain reaction amplification of exon 11 of the D beta H gene followed by digestion of the reaction products with FnuDII (BstUI), we detected a low-frequency restriction fragment length polymorphism (RFLP). The CEPH panel of family DNAs was genotyped for this RFLP, enabling us to determine the linkage relationships between D beta H and four other loci previously mapped to human chromosome 9q. We obtained two-point recombination frequencies (theta) between D beta H and arginosuccinate synthetase (theta = 0, LOD = 7.37), the ABO blood group locus (theta = 0, LOD = 4.5), CRI-P111 (theta = 0, LOD = 2.1), and D9S31 (theta = .06, LOD = 2.81).     

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.     

A novel dysmorphic syndrome with open calvarial sutures and sutural cataracts maps to chromosome 14q13-q21

We describe a new dysmorphic syndrome in an inbred Saudi Arabian family with 21 members. Five males and one female have similar craniofacial features including wide open calvarial sutures with large and late-closing anterior fontanels, frontal bossing, hyperpigmentation with capillary hemangioma of the forehead, significant hypertelorism, and a broad and prominent nose. In addition, these individuals have Y-shaped sutural cataracts diagnosed by 1-2 years of age. No chromosomal or biochemical abnormalities were identified. A genome-wide scan was performed, and two-point LOD score analysis, assuming autosomal recessive inheritance, detected linkage to chromosome 14q13-q21. The highest LOD scores were obtained for marker GATA136A04 (LOD=4.58 at theta=0.00) and for the adjacent telomeric marker D14S1048 (LOD=4.32 at theta=0.00). Multipoint linkage analysis resulted in a maximum LOD score of 5.44 between markers D14S1048 and GATA136A04. Model independent analysis by SIBPAL confirmed linkage to the same chromosomal region. Haplotype analysis indicated that all affected individuals were homozygous for the interval on chromosome 14q13-q21 with two recombinants for D14S1014 (centromeric) and one recombinant for D14S301 (telomeric). These recombinations limit the disease locus to a region of approximately 7.26 Mb. Candidate genes localized to this region were identified, and analysis of PAX9 did not identify mutations in these patients. The unique clinical phenotype and the mapping data suggest that this family represents a novel autosomal recessive syndrome.     

Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations

The aim of this study was to identify regions of the genome that harbor genes influencing inheritance of bicuspid aortic valve (BAV) and/or associated cardiovascular malformation (CVM). Aortic valve disease is an important clinical problem, which often results in valve replacement, the second most common cardiac surgery in the United States. In every age group, a majority of cases of valve disease involves a BAV. BAV is the most common CVM with a reported prevalence of 1–2%. Heritability studies indicate that BAV determination is almost entirely genetic. We used a family-based genome-wide linkage analysis with microsatellite markers. Parametric and nonparametric analyses were performed with the software GENEHUNTER and SOLAR (Sequential Oligogenic Linkage Analysis Routines). Thirty-eight families (353 subjects) with BAV and/or associated CVM were assessed. Each participant underwent a standardized echocardiographic examination. The highest LOD score, 3.8, occurred on chromosome 18q between markers D18S68 and D18S1161. Two other chromosomal regions, 5q15–21 (between D5S644 and D5S2027) and 13q33-qter (between D13S1265 and 13qter), exhibited suggestive evidence of linkage (LOD > 2.0). Further, two previously reported linkage peaks on 9q34 and 17q24 were replicated in family specific analyses. No significant X chromosome linkage peaks were identified. In this genome-wide scan we demonstrate for the first time, that BAV and/or associated CVM exhibit linkage to chromosomes 18q, 5q and 13q. These regions likely contain genes whose mutation results in BAV and/or associated CVM indicating their important role in valvulogenesis and cardiac development. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Lisa J. Martin and Vijaya Ramachandran have contributed equally to this work.     

Localization, by linkage analysis, of the cystinuria type III gene to chromosome 19q13.1.

Cystinuria is an autosomal recessive aminoaciduria in which three urinary phenotypes (I, II, and III) have been described. An amino acid transporter gene, SLC3A1 (formerly rBAT), was found to be responsible for this disorder. Mutational and linkage analysis demonstrated the presence of genetic heterogeneity in which the SLC3A1 gene is responsible for type I cystinuria but not for type II or type III. In this study, we report the identification of the cystinuria type III locus on the long arm of chromosome 19 (19q13.1), obtained after a genomewide search. Pairwise linkage analysis in a series of type III or type II families previously excluded from linkage to the cystinuria type I locus (SLC3A1 gene) revealed a significant maximum LOD score (zeta max) of 13.11 at a maximum recombination fraction (theta max) of .00, with marker D19S225. Multipoint linkage analysis performed with the use of additional markers from the region placed the cystinuria type III locus between D19S414 and D19S220. Preliminary data on type II families also seem to place the disease locus for this rare type of cystinuria at 19q13.1 (significant zeta max = 3.11 at theta max of .00, with marker D19S225).     

Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families

Type 1 diabetes (T1D) is a genetically complex disorder of glucose homeostasis that results from the autoimmune destruction of the insulin-secreting cells of the pancreas. Two previous whole-genome scans for linkage to T1D in 187 and 356 families containing affected sib pairs (ASPs) yielded apparently conflicting results, despite partial overlap in the families analyzed. However, each of these studies individually lacked power to detect loci with locus-specific disease prevalence/sib-risk ratios (lambda(s)) <1.4. In the present study, a third genome scan was performed using a new collection of 225 multiplex families with T1D, and the data from all three of these genome scans were merged and analyzed jointly. The combined sample of 831 ASPs, all with both parents genotyped, provided 90% power to detect linkage for loci with lambda(s) = 1.3 at P=7.4x10(-4). Three chromosome regions were identified that showed significant evidence of linkage (P<2.2x10(-5); LOD scores >4), 6p21 (IDDM1), 11p15 (IDDM2), 16q22-q24, and four more that showed suggestive evidence (P<7.4x10(-4), LOD scores > or =2.2), 10p11 (IDDM10), 2q31 (IDDM7, IDDM12, and IDDM13), 6q21 (IDDM15), and 1q42. Exploratory analyses, taking into account the presence of specific high-risk HLA genotypes or affected sibs' ages at disease onset, provided evidence of linkage at several additional sites, including the putative IDDM8 locus on chromosome 6q27. Our results indicate that much of the difficulty in mapping T1D susceptibility genes results from inadequate sample sizes, and the results point to the value of future international collaborations to assemble and analyze much larger data sets for linkage in complex diseases.