Confirmation of linkage of prostate cancer aggressiveness with chromosome 19q

Regions on chromosomes 7 and 19 were recently reported to contain susceptibility loci that regulate tumor aggressiveness of prostate cancer. To confirm these findings, we analyzed genome scan data from 161 pedigrees affected with prostate cancer. Using the Gleason score as a quantitative measure of tumor aggressiveness, we regressed the squared trait difference, as well as the mean-corrected cross product, on the estimated proportion of alleles shared identical-by-descent at each marker position. Our results confirm the previous linkage results for chromosome 19q (D19S902, P<.00001). In addition, we report suggestive evidence for linkage on chromosome 4 (D4S403, P=.00012). The results of previous findings, together with our results, provide strong evidence that chromosome 19 harbors a gene for tumor aggressiveness.     

Fine-mapping the putative chromosome 17q21–22 prostate cancer susceptibility gene to a 10 cM region based on linkage analysis

Prostate cancer linkage studies have suggested the existence of a prostate cancer susceptibility gene on chromosome 17q21–22. We now report the results of an extended linkage analysis including 95 new multiplex prostate cancer families and 9 additional microsatellite markers resulting in a maximum LOD score of 2.99 at approximately 81–82 cM for all 453 pedigrees. Results from these 95 new pedigrees provide additional support for a chromosome 17q21–22 prostate cancer susceptibility gene. Inclusion of the 9 additional markers significantly reduced the size of the candidate region, as defined using a 1-LOD support interval, especially when focusing analyses on subsets of pedigrees with four or more confirmed affecteds or average age of diagnosis less than or equal to 65 years. A novel subset analysis of only those families (n = 147) that had four or more prostate cancer cases and an average age of prostate cancer diagnosis ≤ 65 years results in a maximum LOD score of 5.49 at 78 cM with a 1-LOD support interval of 10 cM. This large set of pedigrees with four more prostate cancer cases characterized by early-onset disease will serve as a useful resource for identifying the putative 17q21–22 prostate cancer susceptibility gene.     

Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics

While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1–14.3 (LOD = 2.4), and 20p11.21–q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13–22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives. The names of all authors and their affiliations are listed in the Acknowledgements. The fact that Dr Schaid’s name is given here for purposes of correspondence should not be taken to imply that he played the sole leading part in writing this article. An erratum to this article can be found at     

Variants in the HEPSIN gene are associated with prostate cancer in men of European origin

There is considerable evidence that genetic factors are involved in prostate cancer susceptibility. We have studied the association of 11 single nucleotide polymorphisms (SNPs) in the HEPSIN gene (HPN) with prostate cancer in men of European ancestry. HPN is a likely candidate in prostate cancer susceptibility, as it encodes a transmembrane cell surface serum protease, which is overexpressed in prostate cancer; HPN is also located on 19q11–q13.2, where linkage is found with prostate cancer susceptibility. In this case-control association study (590 men with histologically verified prostate cancer and 576 unrelated controls, all of European descent), we find significant allele frequency differences between cases and controls at five SNPs that are located contiguously within the gene. A major 11-locus haplotype is significantly associated, which provides further support that HPN is a potentially important candidate gene involved in prostate cancer susceptibility. Association of one of the SNPs with Gleason score is also suggestive of a plausible role of HPN in tumor aggressiveness.     

Genome-wide linkage scan for prostate cancer susceptibility genes in men with aggressive disease: significant evidence for linkage at chromosome 15q12

Epidemiological and twin studies have consistently demonstrated a strong genetic component to prostate cancer (PCa) susceptibility. To date, numerous linkage studies have been performed to identify chromosomal regions containing PCa susceptibility genes. Unfortunately, results from these studies have failed to form any obvious consensus regarding which regions are most likely to contain genes that may contribute to PCa predisposition. One plausible explanation for the difficulty in mapping susceptibility loci is the existence of considerable heterogeneity in the phenotype of PCa, with significant variation in clinical stage and grade of disease even among family members. To address this issue, we performed a genome-wide linkage scan on 71 informative families with two or more men with aggressive PCa. When only men with aggressive PCa were coded as affected, statistically significant evidence for linkage at chromosome 15q12 was detected (LOD=3.49; genome-wide p=0.005). Furthermore, the evidence for linkage increased when analyses were restricted to Caucasian–American pedigrees (n=65; LOD=4.05) and pedigrees with two confirmed aggressive cases (n=42, LOD=4.76). Interestingly, a 1-LOD support interval about our peak at 15q12 overlaps a region of suggestive linkage, 15q11, identified by a recent linkage study on 1,233 PCa families by the International Consortium for Prostate Cancer Genetics. Using a more rigid definition of PCa in linkage studies will result in a severe reduction in sample sizes available for study, but may ultimately prove to increase statistical power to detect susceptibility genes for this multigenic trait.     

Analysis of HPC1, HPCX, and PCaP in Icelandic hereditary prostate cancer

Putative prostate cancer susceptibility loci have recently been identified by genetic linkage analysis on chromosomes 1q24-25 (HPC1). 1q44.243 (PCaP), and Xq27-28 (HPCX). In order to estimate the genetic linkage in Icelandic prostate cancer families, we genotyped 241 samples from 87 families with eleven markers in the HPC1 region, six markers at PCaP, and eight at HPCX. Concurrently, we assessed allelic imbalance at the HPC1 and PCaP loci in selected tumors from the patients. For each of the candidate regions, the combined parametric and non-parametric LOD scores were strongly negative. Evidence for linkage allowing for genetic heterogeneity was also insignificant for all the regions. The results were negative irrespective of whether calculations were performed for the whole material or for a selected set of early age at onset families. The prevalence of allelic imbalance was relatively low in both the HPC1 (0%-9%) and PCaP (5%-20%) regions and was not elevated in tumors from positively linked families. Our studies indicate that the putative cancer susceptibility genes at chromosomes 1q24-25, 1q44.2-43, and Xq27-28 are unlikely to contribute significantly to hereditary prostate cancer in Iceland and that selective loss of the HPC1 and PCaP loci is a relatively rare somatic event in prostate cancers.     

Genome scans provide evidence for low-HDL-C loci on chromosomes 8q23, 16q24.1-24.2, and 20q13.11 in Finnish families

We performed a genomewide scan for genes that predispose to low serum HDL cholesterol (HDL-C) in 25 well-defined Finnish families that were ascertained for familial low HDL-C and premature coronary heart disease. The potential loci for low HDL-C that were identified initially were tested in an independent sample group of 29 Finnish families that were ascertained for familial combined hyperlipidemia (FCHL), expressing low HDL-C as one component trait. The data from the previous genome scan were also reanalyzed for this trait. We found evidence for linkage between the low-HDL-C trait and three loci, in a pooled data analysis of families with low HDL-C and FCHL. The strongest statistical evidence was obtained at a locus on chromosome 8q23, with a two-point LOD score of 4.7 under a recessive mode of inheritance and a multipoint LOD score of 3.3. Evidence for linkage also emerged for loci on chromosomes 16q24.1-24.2 and 20q13.11, the latter representing a recently characterized region for type 2 diabetes. Besides these three loci, loci on chromosomes 2p and 3p showed linkage in the families with low HDL-C and a locus on 2ptel in the families with FCHL.     

A genome-wide association study of prostate cancer in West African men

Age-adjusted mortality rates for prostate cancer are higher for African-American men compared with those of European ancestry. Recent data suggest that West African men also have elevated risk for prostate cancer relative to European men. Genetic susceptibility to prostate cancer could account for part of this difference. We conducted a genome-wide association study (GWAS) of prostate cancer in West African men in the Ghana Prostate Study. Association testing was performed using multivariable logistic regression adjusted for age and genetic ancestry for 474 prostate cancer cases and 458 population-based controls on the Illumina HumanOmni-5 Quad BeadChip. The most promising association was at 10p14 within an intron of a long non-coding RNA (lncRNA RP11-543F8.2) 360 kb centromeric of GATA3 (p = 1.29E?7). In sub-analyses, SNPs at 5q31.3 were associated with high Gleason score (≥7) cancers, the strongest of which was a missense SNP in PCDHA1 (rs34575154, p = 3.66E?8), and SNPs at Xq28 (rs985081, p = 8.66E?9) and 6q21 (rs2185710, p = 5.95E?8) were associated with low Gleason score (<7) cancers. We sought to validate our findings in silico in the African Ancestry Prostate Cancer GWAS Consortium, but only one SNP, at 10p14, replicated at p < 0.05. Of the 90 prostate cancer loci reported from studies of men of European, Asian or African-American ancestry, we were able to test 81 in the Ghana Prostate Study, and 10 of these replicated at p < 0.05. Further genetic studies of prostate cancer in West African men are needed to confirm our promising susceptibility loci.     

Trait components provide tools to dissect the genetic susceptibility of migraine

The commonly used "end diagnosis" phenotype that is adopted in linkage and association studies of complex traits is likely to represent an oversimplified model of the genetic background of a disease. This is also likely to be the case for common types of migraine, for which no convincingly associated genetic variants have been reported. In headache disorders, most genetic studies have used end diagnoses of the International Headache Society (IHS) classification as phenotypes. Here, we introduce an alternative strategy; we use trait components--individual clinical symptoms of migraine--to determine affection status in genomewide linkage analyses of migraine-affected families. We identified linkage between several traits and markers on chromosome 4q24 (highest LOD score under locus heterogeneity [HLOD] 4.52), a locus we previously reported to be linked to the end diagnosis migraine with aura. The pulsation trait identified a novel locus on 17p13 (HLOD 4.65). Additionally, a trait combination phenotype (IHS full criteria) revealed a locus on 18q12 (HLOD 3.29), and the age at onset trait revealed a locus on 4q28 (HLOD 2.99). Furthermore, suggestive or nearly suggestive evidence of linkage to four additional loci was observed with the traits phonophobia (10q22) and aggravation by physical exercise (12q21, 15q14, and Xp21), and, interestingly, these loci have been linked to migraine in previous studies. Our findings suggest that the use of symptom components of migraine instead of the end diagnosis provides a useful tool in stratifying the sample for genetic studies.     

Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4

As with many complex genetic diseases, genome scans for prostate cancer have given conflicting results, often failing to provide replication of previous findings. One factor contributing to the lack of consistency across studies is locus heterogeneity, which can weaken or even eliminate evidence for linkage that is present only in a subset of families. Currently, most analyses either fail to account for locus heterogeneity or attempt to account for it only by partitioning data sets into smaller and smaller portions. In the present study, we model locus heterogeneity among affected sib pairs with prostate cancer by including covariates in the linkage analysis that serve as surrogate measures of between-family linkage differences. The model is a modification of the Olson conditional logistic model for affected relative pairs. By including Gleason score, age at onset, male-to-male transmission, and/or number of affected first-degree family members as covariates, we detected linkage near three locations that were previously identified by linkage (1q24-25 [HPC1; LOD score 3.25, P=.00012], 1q42.2-43 [PCAP; LOD score 2.84, P=.0030], and 4q [LOD score 2.80, P=.00038]), near the androgen-receptor locus on Xq12-13 (AR; LOD score 3.06, P=.00053), and at five new locations (LOD score > 2.5). Without covariates, only a few weak-to-moderate linkage signals were found, none of which replicate findings of previous genome scans. We conclude that covariate-based linkage analysis greatly improves the likelihood that linked regions will be found by incorporation of information about heterogeneity within the sample.     

Stratification by CARD15 variant genotype in a genome-wide search for inflammatory bowel disease susceptibility loci

Previously we have conducted a genome-wide search for inflammatory bowel disease susceptibility loci in a large European cohort. Results from this study demonstrated suggestive evidence of linkage to loci at chromosomes 1q, 6p, and 10p and replicated linkages on chromosomes 12 and 16. Recently, NOD2/CARD15 on chromosome 16q12 has been found to be strongly associated with Crohn's disease. In order to determine if there are other loci in the genome that interact with the three associated functional variants in CARD15 (R702W, G908R, 1007fs), we have stratified our large inflammatory bowel disease genome scan cohort by dividing pedigrees into two groups stratified by CARD15 variant genotype. The two pedigree groups were analysed using non-parametric allele sharing methods. The group of pedigrees that contained one of the three CARD15 variants had two suggestive linkage results occurring in 6p (lod = 3.06 at D6S197, IBD phenotype) and 10p (lod=2.29 at D10S197, CD phenotype). In addition, at 16q12 where CARD15 is located, the original genome scan had a peak lod score of 2.18 at D16S415 (CD phenotype). The stratified pedigree cohort containing one of three CARD15 variants had a peak lod score of 0.90 at D16S415 (CD phenotype), accounting for approximately less than half of the genetic evidence for linkage at this locus. This result is in agreement with the existence of a substantial number of private variants at the NOD2/CARD15 locus. Interaction with NOD2/CARD15 needs to be considered in future gene identification efforts on chromosomes 6 and 10.     

QTL analysis of leaf morphology in tetraploid Gossypium (cotton)

Molecular markers were used to map and characterize quantitative trait loci (QTLs) determining cotton leaf morphology and other traits, in 180 F₂ plants from an interspecific cross between a Gossypium hirsutum genotype carrying four morphological mutants, and a wild-type Gossypium barbadense. The prominent effects of a single region of chromosome 15, presumably the classical ”Okra-leaf” locus, were modified by QTLs on several other chromosomes affecting leaf size and shape. For most traits, each parent contained some alleles with positive effects and others with negative effects, suggesting a large potential for adapting leaf size and shape to the needs of particular production regimes. Twenty one QTLs/loci were found for the morphological traits at LOD≥3.0 and P≤0.001, among which 14 (63.6%) mapped to D-subgenome chromosomes. Forty one more possible QTLs/loci were suggested with 2.0≤LOD<3.0 and 0.001<P≤0.01. Among all of the 62 possible QTLs (found at LOD≥2.0 and P≤0.01) for the 14 morphological traits in this study, 38 (61.3%) mapped to D-subgenome chromosomes. This reinforces the findings of several other studies in suggesting that the D-subgenome of tetraploid cotton has been subject to a relatively greater rate of evolution than the A-subgenome, subsequent to polyploid formation. Received: 26 April 1999 / Accepted: 30 July 1999     

An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians.

Genetic factors influence the development of type II diabetes mellitus, but genetic loci for the most common forms of diabetes have not been identified. A genomic scan was conducted to identify loci linked to diabetes and body-mass index (BMI) in Pima Indians, a Native American population with a high prevalence of type II diabetes. Among 264 nuclear families containing 966 siblings, 516 autosomal markers with a median distance between adjacent markers of 6.4 cM were genotyped. Variance-components methods were used to test for linkage with an age-adjusted diabetes score and with BMI. In multipoint analyses, the strongest evidence for linkage with age-adjusted diabetes (LOD = 1.7) was on chromosome 11q, in the region that was also linked most strongly with BMI (LOD = 3.6). Bivariate linkage analyses strongly rejected both the null hypothesis of no linkage with either trait and the null hypothesis of no contribution of the locus to the covariation among the two traits. Sib-pair analyses suggest additional potential diabetes-susceptibility loci on chromosomes 1q and 7q.     

Systemic lupus erythematosus susceptibility loci defined by genome scan meta-analysis

To date, several susceptibility loci for systemic lupus erythematosus (SLE) have been identified by individual genome-wide scans, but many of these loci have shown inconsistent results across studies. Additionally, many individual studies are at the lower limit of acceptable power recommended for declaring significant linkage. The genome search meta-analysis (GSMA) has been proposed as a valid and robust method for combining several genome scan results. The aim of this study is to investigate whether there is any consistent evidence of linkage across multiple studies, and to identify novel SLE susceptibility loci by using GSMA method. Twelve genome scan results generated from nine independent studies have been used for the present GSMA. All together, the data consists of 605 families with 1,355 SLE affected individuals from three self-reported ethnicities; Caucasian, African-American, and Hispanic. For each study, the genome was divided into 120 bins (30 cM) and ranked according to the maximum evidence of linkage within each bin. The ranks were summed and averaged across studies following which the significance was assessed by the permutation tests. The present study identified two genomic locations at 6p22.3–6p21.1 and 16p12.3–16q12.2 that met genome-wide significance (p<0.000417). The identified region at 6p22.3–6p21.1 contains the HLA region. The combined p-values using Fisher’s method also supported the significance in these regions. Clustering of significant adjacent bins was observed for chromosomes 6 and 16. Additionally, there are 12 other bins with two point-wise p-values (Psumrnk and Pord) <0.05, suggesting that these bin regions are highly likely to contain SLE susceptibility loci. Among them, present GSMA also identified two novel regions at 4q32.1–4q34.3 and 13q13.2–13q22.2. However, separate analysis using only Caucasian populations identified the strongest evidence for linkage at chromosome 6p21.1–6q15 (Psumrnk=0.00021). One interesting novel region suggests that 3q22.1–3q25.33 (Psumrnk=0.01376) may be an ethnicity-specific SLE linkage. In summary, the present GSMA have identified two statistically significant genomic regions that reconfirmed the SLE linkage at chromosomes 6 and 16.     

Linkage analyses at the chromosome 1 loci 1q24-25 (HPC1), 1q42.2-43 (PCAP), and 1p36 (CAPB) in families with hereditary prostate cancer

Recent studies suggest that hereditary prostate cancer (PRCA) is a complex disease, involving multiple susceptibility genes and variable phenotypic expression. Through linkage analysis, potential prostate cancer susceptibility loci have been mapped to 3 regions on chromosome 1. To investigate the reported linkage to these regions, we conducted linkage studies on 144 PRCA families by using microsatellite markers in regions 1q24-25 (HPC1) and 1q42.2-43 (PCAP). We also examined the 1p36 (CAPB) region in 13 PRCA families with at least one case of brain cancer. No significant evidence of linkage to the HPC1 or PCAP region was found when the entire data set was analyzed. However, weak evidence for linkage to HPC1 was observed in the subset of families with male-to-male transmission (n=102; maximum multipoint nonparametric linkage [NPL] 1.99, P=.03). Weak evidence for linkage with heterogeneity within this subset was also observed (HLOD 1.21, P=.02), with approximately 20% of families linked. Although not statistically significant, suggestive evidence for linkage to PCAP was observed for the families (n=21) that met the three criteria of male-to-male transmission, average age of diagnosis <66 years, and >/=5 affected individuals (maximum multipoint NPL 1.45, P=.08). There was no evidence for linkage to CAPB in the brain cancer-prostate cancer subset. These results strengthen the argument that prostate cancer is a heterogeneous disease and that multiple genetic and environmental factors may be important for its etiology.     

Applying novel genome-wide linkage strategies to search for loci influencing type 2 diabetes and adult height in American Samoa

Type 2 diabetes mellitus (T2DM) is a common complex phenotype that by the year 2010 is predicted to affect 221 million people globally. In the present study we performed a genome-wide linkage scan using the allele-sharing statistic Sall implemented in Allegro and a novel two-dimensional genome-wide strategy implemented in Merloc that searches for pairwise interaction between genetic markers located on different chromosomes linked to T2DM. In addition, we used a robust score statistic from the newly developed QTL-ALL software to search for linkage to variation in adult height. The strategies were applied to a study sample consisting of 238 sib-pairs affected with T2DM from American Samoa. We did not detect any genome-wide significant susceptibility loci for T2DM. However, our two-dimensional linkage investigation detected several loci pairs of interest, including 11q22 and 21q21, 9q21 and 11q22, 1p22-p21 and 4p15, and 4p15 and 15q11-q14, with a two-loci maximum LOD score (MLS) greater than 2.00. Most detected individual loci have previously been identified as susceptibility loci for diabetes-related traits. Our two-dimensional linkage results may facilitate the selection of potential candidate genes and molecular pathways for further diabetes studies because these results, besides providing candidate loci, also demonstrate that polygenic effects may play an important role in T2DM. Linkage was detected (p value of 0.005) for variation in adult height on chromosome 9q31, which was reported previously in other populations. Our finding suggests that the 9q31 region may be a strong quantitative trait locus for adult height, which is likely to be of importance across populations.     

Genetic linkage map of a wheat×spelt cross

 We constructed a genetic map of a cross between the Swiss winter wheat (Triticum aestivum L.) variety Forno and the Swiss winter spelt (Triticum spelta L.) variety Oberkulmer. For the linkage analysis,176 polymorphic RFLP probes and nine microsatellites were tested on 204 F₅ recombinant inbred lines (RILs) of Forno×Oberkulmer revealing 242 segregating marker loci. Thirty five percent of these loci showed significant (P>0.05) deviation from a 1 : 1 segregation, and the percentage of Forno alleles ranged from 21% to 83% for individual marker loci. Linkage analysis was performed with the program MAPMAKER using the Haldane mapping function. Using a LOD threshold of 10, we obtained 37 linkage groups. After finding the best order of marker loci within linkage groups by multi-point analysis we assembled the linkage groups into 23 larger units by lowering the LOD threshold. All except one of the 23 new linkage groups could be assigned to physical chromosomes or chromosome arms according to hybridisation patterns of nulli-tetrasomic lines of Chinese Spring and published wheat maps. This resulted in a genetic map comprising 230 marker loci and spanning 2469 cM. Since the analysed population is segregating for a wide range of agronomically important traits, this genetic map is an ideal basis for the identification of quantitative trait loci (QTLs) for these traits. Received: 3 August 1998 / Accepted: 28 November 1998     

Mapping of a Further Malignant Hyperthermia Susceptibility Locus to Chromosome 3q13.1

Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disease for which MH susceptibility (MHS) is transmitted as an autosomal dominant trait. A potentially life-threatening MH crisis is triggered by exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants. The first malignant hyperthermia susceptibility locus (MHS1) was identified on human chromosome 19q13.1, and evidence has been obtained that defects in the gene for the calcium-release channel of skeletal muscle sarcoplasmic reticulum (ryanodine receptor; RYR1) can cause some forms of MH. However, MH has been shown to be genetically heterogeneous, and additional loci on chromosomes 17q and 7q have been suggested. In a collaborative search of the human genome with polymorphic microsatellite markers, we now found linkage of the MHS phenotype, as assessed by the European in vitro contracture test protocol, to markers defining a 1-cM interval on chromosome 3q13.1. A maximum multipoint lod score of 3.22 was obtained in a single German pedigree with classical MH, and none of the other pedigrees investigated in this study showed linkage to this region. Linkage to both MHS1/RYR1 and putative loci on chromosome 17q and 7q were excluded. This study supports the view that considerable genetic heterogeneity exists in MH.     

Confirmation of the HPCX prostate cancer predisposition locus in large Utah prostate cancer pedigrees

Several genetic predisposition loci for prostate cancer have been identified through linkage analysis, and it is now generally recognized that no single gene is responsible for more than a small proportion of prostate cancers. However, published confirmations of these loci have been few, and failures to confirm have been frequent. The genetic etiology of prostate cancer is clearly complex and includes significant genetic heterogeneity, phenocopies, and reduced penetrance. Powerful analyses that involve robust statistics and methods to reduce genetic heterogeneity are therefore necessary. We have performed linkage analysis on 143 Utah pedigrees for the previously published Xq27-28 (HPCX) prostate cancer susceptibility locus. We employed a robust multipoint statistic (TLOD) and a novel splitting algorithm to reduce intra-familial heterogeneity by iteratively removing the top generation from the large Utah pedigrees. In a dataset containing pedigrees having no more than five generations, we observed a multipoint TLOD of 2.74 (P=0.0002), which is statistically significant after correction for multiple testing. For both the full-structure pedigrees (up to seven generations) and the smaller sub-pedigrees, the linkage evidence was much reduced. This study thus represents the first significant confirmation of HPCX (Xq27-28) and argues for the continued utility of large pedigrees in linkage analyses for complex diseases.     

Genomewide search in familial Paget disease of bone shows evidence of genetic heterogeneity with candidate loci on chromosomes 2q36, 10p13, and 5q35

Paget disease of bone (PDB) is a common disorder characterized by focal abnormalities of increased and disorganized bone turnover. Genetic factors are important in the pathogenesis of PDB, and previous studies have shown that the PDB-like bone dysplasia familial expansile osteolysis is caused by activating mutations in the TNFRSF11A gene that encodes receptor activator of nuclear factor kappa B (RANK); however, linkage studies, coupled with mutation screening, have excluded involvement of RANK in the vast majority of patients with PDB. To identify other candidate loci for PDB, we conducted a genomewide search in 319 individuals, from 62 kindreds with familial PDB, who were predominantly of British descent. The pattern of inheritance in the study group as a whole was consistent with autosomal dominant transmission of the disease. Parametric multipoint linkage analysis, under a model of heterogeneity, identified three chromosomal regions with LOD scores above the threshold for suggestive linkage. These were on chromosomes 2q36 (LOD score 2.7 at 218.24 cM), 5q35 (LOD score 3.0 at 189.63 cM), and 10p13 (LOD score 2.6 at 41.43 cM). For each of these loci, formal heterogeneity testing with HOMOG supported a model of linkage with heterogeneity, as opposed to no linkage or linkage with homogeneity. Two-point linkage analysis with a series of markers from the 5q35 region in another large kindred with autosomal dominant familial PDB also supported linkage to the candidate region with a maximum LOD score of 3.47 at D5S2034 (187.8 cM). These data indicate the presence of several susceptibility loci for PDB and identify a strong candidate locus for the disease, on chromosome 5q35.