Family Linkage Research Articles

Studying the genetics of Hirschsprung's disease: unraveling an oligogenic disorder

Hirschsprung's disease is characterized by the absence of ganglion cells in the myenteric and submucosal plexuses of the gastrointestinal tract. Genetic dissection was successful as nine genes and four loci for Hirschsprung's disease susceptibility were identified. Different approaches were used to find these loci such as classical linkage in large families, identity by descent mapping in an inbred kindred, candidate gene approaches based on naturally occurring mutant mice models, and finally the use of model-free linkage and association analyzes. In this study, we review the identification of genes and loci involved in the non-syndromic common form and syndromic Mendelian forms of Hirschsprung's disease. The majority of the identified genes are related to Mendelian syndromic forms of Hirschsprung's disease. The non-Mendelian inheritance of sporadic non-syndromic Hirschsprung's disease proved to be complex; involvement of multiple loci was demonstrated in a multiplicative model. We discuss the practical implications of the elucidation of genes associated with Hirschsprung's disease susceptibility for genetic counseling. Finally, we speculate on possible strategies to identify new genes for Hirschsprung's disease.

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.

Sequence-Based Linkage Analysis

The rapid decrease in the cost of DNA sequencing will enable its use for novel applications. Here, we investigate the use of DNA sequencing for simultaneous discovery and genotyping of polymorphisms in family linkage studies. In the proposed approach, short contiguous segments of genomic DNA, regularly spaced across the genome, are resequenced in each pedigree member, and all sequence polymorphisms discovered within a pedigree are used as genetic markers. We use computer simulations consistent with observed human sequence diversity to show that segments of 500-1,000 base pairs, spaced at intervals of 1-2 Mb across the genome, provide linkage information that equals or exceeds that of traditional marker-based approaches. We validate these results experimentally by implementing the sequence-based linkage approach for chromosome 19 in CEPH pedigrees.

Frontotemporal dementia: genetics and genetic counseling dilemmas.

Frontotemporal dementia (FTD) is a neurodegenerative disease with early symptoms of personality change and/or language disorder. Approximately 40% of individuals with FTD have a family history of dementia; however, in our experience, less than 10% have clear autosomal dominant inheritance. Mutations in the microtubule-associated protein tau (MAPT) gene have been reported in up to 50% of hereditary cases, but are unusual except in families with more than 3 individuals with FTD. The genetics of FTD is complicated by clinical heterogeneity, variable expression, phenocopies, misdiagnoses, and lost family histories. The objective of this paper is to enable physicians to recognize hereditary patterns and genetic concerns of FTD families and to understand genetic counseling strategies. The complexity of FTD genetics and genetic counseling are illustrated using 4 case histories. Case 1 demonstrates the difficulty obtaining a reliable FTD family history. Case 2 illustrates how psychiatric phenocopies can make family linkage studies difficult. The lack of genotype and phenotype correlation and issues of predictive genetic testing within FTD families are the subject of case 3, and case 4 shows how normal aging language difficulties and cognitive changes can be misinterpreted when a family history of dementia is present. Physicians seeing patients with possible FTD should be aware of the risk of a genetic etiology. A 3-generation family history should be obtained with attention to neurologic, psychiatric, and behavioral symptoms. Variable expression and phenocopies are confounding factors when assessing a possible genetic etiology. Referral of the patient and family for genetic counseling is recommended.

Genetic determinants of bone mass.

This review examines recent advances in the analysis of genetic determinants of bone mass. It addresses both human and animal linkage studies as well as genetic manipulations in animals, inbred mouse models, and candidate gene analyses. Recent studies have implicated novel regulatory pathways in bone biology including both the neuroendocrine system and metabolic pathways linked to lipid metabolism. Variations in the lipoprotein receptor-related protein 5 (LRP5), part of the Wnt-frizzled pathway, were independently identified by linkage in high and low bone mass families. Subsequently, other high bone mass syndromes have been shown to have mutations in this gene. Neural studies have shown the skeletal regulatory activity of leptin and neuropeptide Y receptors via the hypothalamus. Subsequently, the beta-adrenergic pathway has been implicated, with important changes in bone mass. The lipoxygenase 12/15 pathway, identified through inbred mouse models and through pharmacologic studies with specific inhibitors, has also been shown to have important effects on bone mass. These studies exemplify the value of genetic models both to identify and then confirm pathways by mutational study and pharmacologic interventions. Continuing candidate gene studies often performed with multiple loci complement such discoveries. However, these studies have not focused on the clinical endpoint of fracture and few have included large enough groups to engender confidence in the associations reported, as such studies may require thousands of individuals. Interestingly, results often differ by ethnicity, age, or gender. A small proportion have examined whether relevant genes influence response to treatment. The combinations of human and animal genetic linkage studies have advanced understanding of the regulation of bone mass. Studies ranging from linkage to pharmacology provide optimism for new targets and treatments for osteoporosis.

Familial Wilms tumor.

Wilms tumor (WT), an embryonic tumor arising from undifferentiated renal mesenchyme, has been a productive model for understanding the role of genes in both tumorigenesis and normal organogenesis. Approximately 2% of WT patients have a family history of WT, and even sporadic WT is thought to have a strong genetic component to its etiology. Familial WT cases generally have an earlier age of onset and an increased frequency of bilateral disease, although there is variability among WT families, with some families displaying later than average ages at diagnosis. One WT gene, WT1 at 11p13, has been cloned, but only a minority of tumors carry detectable mutations at that locus, and it can be excluded as the predisposition gene in most WT families. Two familial WT genes have been localized, FWT1 at 17q12-q21 and FWT2 at 19q13.4; lack of linkage in some WT families to either of these loci implies the existence of at least one additional familial WT gene. Originally modeled as the inheritance of a mutation in a tumor suppressor gene, molecular analysis of familial tumors not linked to 11p13 have provided data suggesting that this model may be overly simplistic and/or not applicable to all WT families. Identification of the FWT1 and FWT2 genes will help clarify this and will also likely aid in our understanding in general of the roles of the various WT genes and their genetic interactions in the development of WT.

Perspectives on familial chronic lymphocytic leukemia: genes and the environment

Chronic lymphocytic leukemia (CLL) comprises a substantial proportion of leukemias in adults in the western hemisphere. Male gender, increasing age, ethnicity (high in Caucasians, lowest in Asians), and family history are risk factors. Although no specific extrinsic etiologic factors have been established, farming and pesticide exposure are associated with increased risk. Migration studies confirm that ethnic groups retain the risk associated with their origin rather than their new location, favoring a role for heredity. Kindreds with multiple cases of CLL have been well described in the literature and studies in large populations confirm that lymphoproliferative malignancies and especially CLL occur together at a rate that cannot be attributed to chance. Since environmental factors cannot readily explain the familial aggregations, a hereditary factor that affects susceptibility to CLL is likely. The identification of clones that are immunophenotypically identical to CLL in healthy individuals from CLL kindreds (14% to 18%) as well as in the general population (3.5% in age bracket >65 years) suggests a possible precursor condition, but longitudinal studies will be necessary to establish significance in the general population. Family (linkage) and population (candidate gene) studies to date have been too small to identify the specific genes that account for increased susceptibility; larger studies including planned consortia to identify additional high-risk kindreds for genetic studies, as well as the application of advanced technologies such as genomics, cytogenetic, expression, and proteomics, are widely expected to advance understanding over the next few years.

Toward the Last Cohort

Toward the Last Cohort

Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population

To address the possibility that the partial disruption of Glucagon-like peptide-1 (GLP-1) signaling could cause diabetes, we tried to detect the mutation in GLP-1 receptor ( GLP-1R) gene in the population with type 2 diabetes. Genomic DNA was extracted from 36 unrelated Japanese type 2 diabetic subjects and directly sequenced for the GLP-1R gene. For the detected polymorphisms, 791 patients with type 2 diabetes and 318 controls were screened by polymerase chain reaction-restricted fragment length polymorphism and association study was carried out. Five missense and four silent variants were detected in the GLP-1R gene. There were no significant differences in the frequencies of Pro7Leu, Arg44His and Leu260Pro polymorphism between the diabetic and control groups. And also there were no significant differences in body mass index (BMI), onset age and fasting IRI among the wild type, heterozygote and homozygote of these variants in diabetic patients. Thr149Met mutation was detected in one case among 791 type 2 diabetes patients, but not in control subjects. The patient with this mutation exhibited impairment of both insulin secretion, insulin sensitivity and glucose effectiveness, which may be partially explained by Thr149Met mutation in GLP-1R, though family linkage analysis and function analysis remain to be examined.

Erratum: Genome-wide scanning for linkage in Finnish breast cancer families

Correction to: European Journal of Human Genetics (2003); doi: 10.1038/sj.ejhg.5201091 ; Published online 15 October 2003.

Exclusion of an extracolonic disease modifier locus on chromosome 1p33-36 in a large Swiss familial adenomatous polyposis kindred.

Familial adenomatous polyposis (FAP), an autosomal dominantly inherited colorectal cancer predisposition syndrome, displays considerable inter- and intrafamilial phenotypic heterogeneity, which represents a major problem in genetic counselling of APC mutation carriers. The Min mouse model indicated a putative disease modifier locus on chromosome 4, which is syntenic to human chromosome 1p35-36. This finding was subsequently supported by parametric and nonparametric linkage analyses in FAP families, however, without identifying functional variants in candidate genes. Recently, germline mutations in the base-excision repair gene MYH (1p33-34) have been described in patients with multiple adenomas, pointing to a possible role as disease modifier in FAP. Here, we present critical reassessment of one of the largest FAP kindreds published, which was previously used in linkage mapping of 1p35-36. In this family, all affected members harbour the same APC germline mutation (5945delA), but display marked phenotypic variability, in particular regarding the occurrence of extracolonic disease that segregates in several branches of the family tree. Using updated clinical information, additional mutation carriers and polymorphic markers, fine mapping of the critical region as well as mutation analysis of the MYH gene were performed. These investigations allowed us to significantly exclude (i) the 1p33-36 region as a modifier locus and (ii) MYH as a modifier gene for extracolonic disease in this FAP kindred. Our results do not eliminate 1p33-36 from suspicion in other families, but clearly indicate that in our family linkage analysis of further putative candidate regions is necessary to identify a disease modifier locus in FAP.

A multilocus likelihood approach to joint modeling of linkage, parental diplotype and gene order in a full-sib family

BackgroundUnlike a pedigree initiated with two inbred lines, a full-sib family derived from two outbred parents frequently has many different segregation types of markers whose linkage phases are not known prior to linkage analysis.ResultsWe formulate a general model of simultaneously estimating linkage, parental diplotype and gene order through multi-point analysis in a full-sib family. Our model is based on a multinomial mixture model taking into account different diplotypes and gene orders, weighted by their corresponding occurring probabilities. The EM algorithm is implemented to provide the maximum likelihood estimates of the linkage, parental diplotype and gene order over any type of markers.ConclusionsThrough simulation studies, this model is found to be more computationally efficient compared with existing models for linkage mapping. We discuss the extension of the model and its implications for genome mapping in outcrossing species.

A review of the 'Statistical Analysis for Genetic Epidemiology' (SAGE) software package

The 'Statistical Analysis for Genetic Epidemiology' (S.A.G.E.) software package is an integrated, comprehensive package of computer programs designed to perform many of the different analyses required in the study of genetic epidemiology. It offers a graphical user interface for most platforms and, unlike many programs available in the public domain, is flexible in both receiving many types of input files and in allowing the user to choose among output files. All of the programs accept the same data files and together provide the means to perform familial correlation, segregation, linkage and association analyses, as well as many of the ancillary analyses that help achieve these goals. Many, but not all, of the same or similar analyses can be performed (with more difficulty) using publicly available freeware. The primary limitations of S.A.G.E. at present are the lack of software for estimating haplotypes or for identifying probable double recombinants in linkage analysis. S.A.G.E. is continually being extended and upgraded, however, with automatic downloading of the latest version always available to users.

Re-evaluation of the .BETA.-globin gene cluster haplotypes in Japanese, Koreans, and three Colombian Amerinds (Wayuu, Kamsa, and Inga tribes)

The EH program for maximum-likelihood (ML) frequencies based on an expectation-maximization (EM) algorithm was employed for re-estimation of the β-globin gene cluster haplotype frequency distributions in Japanese, Koreans, and three Colombian Amerinds (Wayuu, Kamsa, and Inga tribes). The distributions estimated by the EH program (estimation 3) were compared with those of our previous studies obtained from individuals who were homozygous at all polymorphic restriction sites or heterozygous at only one site (estimation 1), or ascertained by family linkage studies in Japanese and Koreans (estimation 2). Average haplotype diversities and Nei’s genetic distances based on estimation 3 were also compared with those based on estimations 1 and 2. Haplotypes of all chromosomes examined, which were based on RFLPs (restriction fragment length polymorphisms) at five or seven sites in the β-globin gene cluster, were determined by the EH program as in the case of a family linkage study. The average haplotype diversities based on estimation 3 were much higher than those based on estimations 1 and 2. The present study based on estimation 3 confirmed the close genetic relationships between Japanese and Koreans, and also between Wayuu and Kamsa. Colombian Amerinds showed some African or European characteristics as well as those of Asians.

Genome-wide linkage and QTL mapping in porcine F2 families generated from Pietrain, Meishan and Wild Boar crosses

Summary Three informative pig F2 families based on European Wild Boar (W), Meishan (M) and Pietrain (P) crosses have been used for genome-wide linkage and quantitative trait loci (QTL) analysis. Altogether 129 microsatellites, 56 type I loci and 46 trait definitions (specific to growth, fattening, fat deposition, muscling, meat quality, stress resistance and body conformation) were included in the study. In the linkage maps of M × P, W × P and W × M families, average spacing of markers were 18.4, 19.7 and 18.8 cM, the numbers of informative meioses were 582, 534 and 625, and the total lengths of autosomes measured were 27.3, 26.0 and 26.2 Morgan units, respectively. Maternal maps were on average 1.3 times longer than paternal maps. QTLs contributing more than 3% of F2 phenotypic variance could be identified at p < 0.05 chromosome-wide level. Differences in the numbers and positions of QTLs were observed between families. Genome-wide significant QTL effects were mapped for growth and fattening traits on eight chromosomes (1, 2, 4, 13, 14, 17, 18 and X), for fat deposition traits on seven chromosomes (1, 2, 3, 4, 6, 7 and X), for muscling traits on 11 chromosomes (1, 2, 3, 4, 6, 7, 8, 12, 14, 15 and X), for meat quality and stress resistance traits on seven chromosomes (2, 3, 6, 13, 16, 18 and X), and QTLs for body-conformation traits were detected on 14 chromosomes. Closely correlated traits showed similar QTL profiles within families. Major QTL effects for meat quality and stress resistance traits were found on SSC6 in the interval RYR1-A1BG in the W × P and M × P families, and could be attributed to segregation of the RYR1 allele T derived from Pietrain, whereas no effect in the corresponding SSC6 interval was found in family W × M, where Wild Boar and Meishan both contributed the RYR1 allele C. QTL positions were mostly similar in two of the three families for body conformation traits and for growth, fattening, fat deposition and muscling traits, especially on SSC4 (interval SW1073-NGFB). QTLs with large effects were also mapped on SSC7 in the major histocompatibility complex (MHC) (interval CYP21A2-S0102) and affected body length, weight of head and many other traits. The identification of DNA variants in genes causative for the QTLs requires further fine mapping of QTL intervals and a positional cloning. However, for these subsequent steps, the genome-wide QTL mapping in F2 families represents an essential starting point and is therefore significant for animal breeding. Zusammenfassung Drei informative F2-Familien, die aus Kreuzungen von Europaischem Wildschwein (W), Meishan (M) und Pietrain (P) erstellt worden waren, wurden fur eine genomweite Kopplungs- und QTL-Analyse benutzt. Insgesamt wurden 129 Mikrosatellitenloci, 56 Type-I-Loci und 46 Merkmalsdefinitionen (fur Wachstum, Mastleistung, Fettansatz, Bemuskelung, Fleischqualitat, Stressresistenz und Korperform) in die Untersuchungen einbezogen. In den Kopplungskarten der Familien M × P, W × P und W × M wurden durchschnittliche Markerabstande von 18.4, 19.7 bzw. 18.8 cM erreicht und 582, 534 bzw. 625 informative Meiosen beobachtet. Fur die Gesamtlangen der Autosomen wurden in den drei Familien 27.3, 26.0 bzw. 26.2 Morgan-Einheiten gemessen. Die maternalen Kopplungskarten waren durchschnittlich 1.3-fach langer als die paternalen. QTLs, die mehr als 3% der phanotypischen Varianz in der F2-Generation erklarten, konnten mit p < 0.05 chromosomenweitem Signifikanzniveau nachgewiesen werden. Zwischen den Familien wurden Differenzen in den Anzahlen und Positionen der QTLs beobachtet. Genomweit signifikante QTL-Effekte wurden fur Wachstum und Fettansatz auf acht Chromosomen (1, 2, 4, 13, 14, 17, 18 und X) kartiert, fur Fettansatz auf sieben Chromosomen (1, 2, 3, 4, 6, 7 und X), fur Bemuskelung auf elf Chromosomen (1, 2, 3, 4, 6, 7, 8, 12, 14, 15 und X), fur Fleischqualitat/Stressresistenz auf sieben Chromosomen (2, 3, 6, 13, 16, 18 und X), und QTLs fur die Korperform wurden auf 14 Chromosomen kartiert. Eng korrelierte Merkmale zeigten ahnliche QTL-Profile innerhalb Familien. Die bedeutsamsten QTL-Effekte wurden fur Fleischqualitats- und Stressresistenzmerkmale auf Chromosom 6, Intervall RYR1-A1BG, in den Familien W × P und M × P gefunden, wahrend in diesem Chromosomenintervall in der Familie W × M, in der der RYR1-Locus keine segregierenden Exon-Allele aufwies, kein QTL zu erkennen war. Mehrere der QTL-Positionen waren fur die Korperform wie auch fur Wachstum, Mastleistung, Fettansatz und Bemuskelung in zwei von drei Familien ahnlich. Dies galt besonders fur Chromosom 4 (Intervall SW1073-NGFB). QTLs mit grosen Effekten wurden auf Chromosom 7 im MHC (Intervall CYP21A2-S0102) kartiert; sie beeinflussten Korperlange, Kopfgewicht, aber auch viele weitere Merkmale. Zur Identifizierung der DNA-Varianten, die einem QTL zugrunde liegen, ist eine Feinkartierung von QTLs und positionale Klonierung erforderlich. Fur diese nachfolgenden Untersuchungsmethoden ist jedoch die genomweite QTL-Kartierung in F2-Familien ein entscheidender Ausgangspunkt; sie ist deshalb bedeutungsvoll fur die Tierzuchtung.

Ovarian torsion: to pex or not to pex? case report and review of the literature

Study objectiveWe report the case of a 7-year-old girl who underwent laparoscopic ovariopexy for a suspected ovarian torsion after a previous oophorectomy. We consider the role of elective ovariopexy of the contralateral ovary in the case of adnexal torsion. DesignCase study and review of the literature. ResultThere was evidence to suggest a very recent adnexal torsion and an unusually long ovarian pedicle, with a possible familial linkage. The patient underwent laparoscopic ovariopexy for the remaining normal ovary, which was found to be loosely twisted at operation. After detorsion, ovariopexy was performed laparoscopically, by suturing the ovary to the back of uterus. There are no other descriptions in the literature of a familial linkage with ovarian torsion. ConclusionThe case presented reminds doctors of the strong possibility of ovarian torsion in young girls presenting with pelvic pain. Laparoscopic ovariopexy for the contralateral ovary should be considered in all women with evidence of torsion, including children and adolescents, as is standard for testicular torsion.

Caspase 7 is a positional candidate gene for IDDM 17 in a Bedouin Arab family.

The IDDM 17 locus was mapped to an 8-cM interval at chromosome 10q25.1 based on linkage in a large Bedouin Arab family with 19 affected relatives. Caspase 7 (CASP7), an apoptosis-related cysteine protease, is one of the few known genes in this region. CASP7 is involved in the activation cascade of caspases responsible for apoptosis execution. Only 1 of the 18 SNPs in CASP7 (SNP144692) differed significantly in frequency in the haplotypes found in affected individuals compared to control Bedouin haplotypes. This same SNP showed evidence of association with diabetes in a subset of patients (DR3/DR4*0302) from HBDI families.

No evidence for linkage in Swedish multiplex T1DM families to IL12B on chromosome 5q33-34.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which the beta cells in the pancreas are destroyed by the body's own immune system. IL12 plays a role in pathological situations, such as septic shock, tissue damage during inflammation, and organ-specific autoimmune diseases. In NOD mice, administration of IL12 induces T1DM and administration of IL12 antagonists prevents T1DM. Linkage and association of IL12 to T1DM have been reported previously. We are unable to replicate this linkage on chromosome 5q33-34 in 184 Swedish families. Further, we exclude a gene with lambda(s) > 1.4 from this region. Together with previously published findings, these data make IL12 an unlikely major susceptibility gene for T1DM.

Single nucleotide polymorphism study of IDDM 17 in a Bedouin Arab family.

Type 1 diabetes is an autoimmune disease caused by a combination of genetic and environmental factors. On the basis of a genomic search for linkage in a Bedouin Arab family with 19 members with type 1 diabetes, we previously mapped the IDDM 17 locus to the chromosome 10q25.1 region. The result from a recent genome scan showed suggestive evidence of linkage of IDDM 17 in a subset of Caucasian families in which all affected individuals have DR3, indicating that the IDDM 17 locus might have a measurable effect in Caucasian populations from the United Kingdom and the United States. High-resolution SNP typing provides strong evidence of linkage disequilibrium to the IDDM 17 locus.

Genome-wide scan for prostate cancer susceptibility genes in the Johns Hopkins hereditary prostate cancer families.

Although the subject of intensive study, the genetic influences responsible for familial clustering of prostate cancer remain largely unidentified. Genome-wide scans for linkage in prostate cancer families can be used to systematically search for genes capable of affecting risk for the disease. All available family members from 188 families, each having at least three first-degree relatives affected with prostate cancer, were genotyped at 406 markers distributed across the genome at average intervals of less than 10 cM. Genotype data was analyzed using primarily a non-parametric, multipoint approach, although parametric analyses were performed as well. The strongest evidence for linkage was observed at D4S1615, at 4q21 (LOD of 2.8, P = 0.0002). Two other regions had LOD scores over 2.0: at 9q34 (marker D9S1826, LOD = 2.17, P = 0.0008) and at 2q23 (marker D2S151, LOD = 2.03, P = 0.001). An additional 12 regions had LOD scores over 1.0, including markers at 1q24-25 and 7q22 having scores >1.6. Stratifying the linkage results by age of diagnosis indicated that the linkages to chromosomes 2 and 4 were strongest in families with early and late ages of diagnosis, respectively. Our data implicate several new loci as harboring prostate cancer susceptibility genes, and provide confirmatory evidence of linkage at several loci identified previously in other genome-wide scans, including the three regions (4q21, 9q34, and 2q23) with strongest evidence for prostate cancer linkage. These data also emphasize the need to combine linkage data from large numbers of prostate cancer families in efforts to effectively address the extensive heterogeneity that characterizes genetic aspects of this disease.