Biomedical subjects

Nicola J Camp

Publications and source records attributed to Nicola J Camp.

At least 19 recordsLinked to original sources

PubMed2006

A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration.

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a strong genetic predisposition. A locus at human chromosome 10q26 affects the risk of AMD, but the precise gene(s) have not been identified. We genotyped 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah. We demonstrate that a single-nucleotide polymorphism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for AMD at 10q26 and is estimated to confer a population attributable risk of 49.3%. The HTRA1 gene encodes a secreted serine protease. Preliminary analysis of lymphocytes and retinal pigment epithelium from four AMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein. We also found that drusen in the eyes of AMD patients were strongly immunolabeled with HTRA1 antibody. Together, these findings support a key role for HTRA1 in AMD susceptibility and identify a potential new pathway for AMD pathogenesis.

Aged↗

PubMed2006

Localization of a prostate cancer predisposition gene to an 880-kb region on chromosome 22q12.3 in Utah high-risk pedigrees.

Chromosome 22q has become recently a region of interest for prostate cancer. We identified previously a logarithm of odds (LOD) of 2.42 at chromosome 22q12.3. Additionally, this region has been noted by eight other studies, with linkage evidence ranging from LOD of 1.50 to 3.57. Here, we do fine mapping and localization of the region using a pedigree-specific recombinant mapping approach in 14 informative, high-risk Utah pedigrees. These 14 pedigrees were chosen because they were either "linked" or "haplotype-sharing" pedigrees or both. "Linked" pedigrees were those with significant pedigree-specific linkage evidence (LOD, >0.588; P < 0.05) to the 22q12.3 region, regardless of the number of prostate cancer cases sharing the segregating haplotype. "Haplotype-sharing" pedigrees were those with at least five prostate cancer cases sharing a segregating haplotype in the 22q12.3 region, regardless of the linkage evidence. In each pedigree, the most likely haplotype configuration (in addition to the multipoint LOD graph for linked pedigrees) was used to infer the position of recombinant events and delimit the segregating chromosomal segment in each pedigree. These pedigree-specific chromosomal segments were then overlaid to form a consensus recombinant map across all 14 pedigrees. Using this method, we identified a 881,538-bp interval at 22q12.3, between D22S1265 and D22S277, which is the most likely region that contains the 22q prostate cancer predisposition gene. The unique Utah extended high-risk pedigree resource allows this powerful localization approach in pedigrees with evidence for segregating predisposition to prostate cancer. We are mutation screening candidate genes in this region to identify specific genetic variants segregating in these pedigrees.

Aged↗

PubMed2006

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.

Black or African American↗

PubMed2006

PedGenie: an analysis approach for genetic association testing in extended pedigrees and genealogies of arbitrary size.

BACKGROUND: We present a general approach to perform association analyses in pedigrees of arbitrary size and structure, which also allows for a mixture of pedigree members and independent individuals to be analyzed together, to test genetic markers and qualitative or quantitative traits. Our software, PedGenie, uses Monte Carlo significance testing to provide a valid test for related individuals that can be applied to any test statistic, including transmission disequilibrium statistics. Single locus at a time, composite genotype tests, and haplotype analyses may all be performed. We illustrate the validity and functionality of PedGenie using simulated and real data sets. For the real data set, we evaluated the role of two tagging-single nucleotide polymorphisms (tSNPs) in the DNA repair gene, NBS1, and their association with female breast cancer in 462 cases and 572 controls selected to be BRCA1/2 mutation negative from 139 high-risk Utah breast cancer families. RESULTS: The results from PedGenie were shown to be valid both for accurate p-value calculations and consideration of pedigree structure in the simulated data set. A nominally significant association with breast cancer was observed with the NBS1 tSNP rs709816 for carriage of the rare allele (OR = 1.61, 95% CI = 1.10-2.35, p = 0.019). CONCLUSION: PedGenie is a flexible and valid statistical tool that is intuitively simple to understand, makes efficient use of all the data available from pedigrees without requiring trimming, and is flexible to the types of tests to which it can be applied. Further, our analyses of real data indicate NBS1 may play a role in the genetic etiology of heritable breast cancer.

Biomarkers, Tumor↗

PubMed2006

Maximum likelihood estimates of allele frequencies and error rates from samples of related individuals by gene counting.

SUMMARY: Graphical modeling is used to extend the gene counting method to compute maximum likelihood estimates of allele frequencies for samples of individuals related in extended pedigrees. Genotypes may be missing or partially observed, and error rates can be simultaneously estimated. AVAILABILITY: The Java classes and Javadocs pages for \mathsf\hbox GeneCountAlleles can be obtained from bioinformatics.med.utah.edu/~alun, which also has more information on its use and file formats.

Biological Evolution↗

PubMed2006

Evidence for linkage on chromosome 3q25-27 in a large autism extended pedigree.

Though autism shows strong evidence for genetic etiology, specific genes have not yet been found. We tested for linkage in a candidate region on chromosome 3q25-27 first identified in Finnish autism families [1]. The peak in this previous study was at D3S3037 (183.9 cM). We tested this region in seven affected family members and 24 of their relatives from a single large extended Utah pedigree of Northern European ancestry. A total of 70 single nucleotide polymorphisms (SNPs) were analyzed from 165 to 204 cM. The maximum NPL-all nonparametric score using SimWalk2snp was 3.53 (empirical p val ue = 0.0003) at 185.2 cM (SNP rs1402229), close to the Finnish peak. A secondary analysis using MCLINK supported this result, with a maximum of 3.92 at 184.6 cM (SNP rs1362645). We tested for alterations in a candidate gene in this region, the fragile X autosomal homolog, FXR1. No variants likely to contribute to autism were found in the coding sequence, exon-intron boundaries, or the promoter region of this gene.

Adolescent↗

PubMed2006

Identification of excess clustering of coronary heart diseases among extended pedigrees in a genealogical population database.

BACKGROUND: First-degree family history of early coronary artery disease (CAD) and myocardial infarction (MI) is prognostic among disease-free individuals but may be unreliable. This study evaluated deaths caused by CAD, MI, hypertensive heart disease (HtnHD), and congestive heart failure (CHF) among close and distant relatives. METHODS: The Utah Population Database contains >2.2 million individual records with genealogy data and 250,000 linked death certificates. Deaths caused by CAD (n = 28,469), MI (n = 26,468), HtnHD (n = 3933), and CHF (n = 11,784) were studied. Familial relative risks (FRRs) were assessed for first- and second-degree relatives. Familiality was also evaluated using the Genealogical Index of Familiality (GIF), which considers close and distant genetic relationships in the Utah Population Database. RESULTS: Familial relative risks in first-degree (FRR = 1.25, P < .0001) and second-degree (FRR = 1.06, P = .0002) relatives were significant for early age at MI death (<65 years old). Genealogical Index of Familiality analysis demonstrated excess relatedness for deaths caused by MI (case GIF 2.93, mean control GIF 2.73, P < .001) and CHF (2.92 vs 2.66, P < .001). For early age at death, GIFs were significant for MI (3.06 vs 2.54, P < .001), HtnHD (3.22 vs 2.44, P = .003), and CHF (2.64 vs 2.23, P = .003). CONCLUSIONS: Deaths caused by MI and CHF demonstrate a heritable component in close and distant relatives. For MI, CHF, and HtnHD, for which findings were more pronounced in early age at death, gene discovery may be most effective among early-onset clusters. Excess relatedness was not found for CAD death--perhaps because of heterogeneity within the phenotype--suggesting that this may be a suboptimal phenotype for genetic study.

Adult↗

PubMed2006

High-resolution characterization of linkage disequilibrium structure and selection of tagging single nucleotide polymorphisms: application to the cholesteryl ester transfer protein gene.

Full characterization of intragenic variation may improve candidate gene associations. This study selected tagging (t) single nucleotide polymorphisms (SNPs) to comprehensively represent genetic variability in the cholesteryl ester transfer protein (CETP) gene. Nineteen SNPs were identified in 50 unrelated individuals in the SNP discovery phase, and 13 intronic SNPs were added from the literature. These 32 SNPs were genotyped in 339 apparently healthy individuals and 190 coronary artery disease (CAD) patients. Using phased haplotypes, linkage disequilibrium (LD) structure was characterized and tSNPs selected using a principal component analysis (PCA) method. In healthy individuals, seven LD groups were identified that accounted for 93.4% of the observed genetic variation. These LD groups highlighted a complex LD structure for CETP, including both recombination and mutation, and eleven tSNPs were selected. Among CAD patients the results were essentially the same. Results from PCA using diploid genotype data were reasonably comparable. Finally, the selected tSNPs successfully represented the association evidence discovered for all of the other SNPs studied. This study provides an optimal set of tSNPs for association analyses of CETP. The observed complexity of LD structure highlights the importance of using methods, such as PCA, that allow for multiple dynamics in intragenic LD structure.

Aged↗

PubMed2006

A role for XRCC4 in age at diagnosis and breast cancer risk.

Genetic variants in DNA repair genes influence the ability to repair damaged DNA. Unrepaired or improperly repaired DNA may lead to genetic instability and carcinogenesis. We evaluated the role of four tagging single nucleotide polymorphisms (tSNP) in the DNA repair gene, XRCC4, and its association with breast cancer risk and age at diagnosis of breast cancer in 464 cases and 576 controls selected to be BRCA1/2 mutation negative from high-risk Utah pedigrees. We observed a significant association for two 4-locus tSNP haplotypes and age at diagnosis. Carriage of one haplotype was associated with later diagnosis (haplotype frequency, 0.039; mean age at diagnosis, 67.17 years; P = 0.001), and carriage of the other was associated with earlier diagnosis (haplotype frequency, 0.214; mean age at diagnosis, 54.04 years; P = 0.0085). For breast cancer risk, two 2-locus tSNP haplotypes explained the observed association as well as extended four-locus haplotypes. The two 2-locus haplotypes were nominally associated with breast cancer risk, one for reduced risk (odds ratio, 0.57; 95% confidence interval, 0.36-0.90; P = 0.014) and one for increased risk (odds ratio, 1.30; 95% confidence interval, 1.02-1.67; P = 0.033). Moreover, one of the tSNPs is in strong linkage disequilibrium (D' = 1.00) with an XRCC4 SNP found to be significantly associated with breast cancer risk in Taiwan, hence, confirming their findings. Our results suggest that XRCC4 may play a role in the age at diagnosis and risk of breast cancer in non-BRCA1/2, heritable breast cancer cases.

Age of Onset↗

PubMed2005

Genomic search for prostate cancer predisposition loci in Utah pedigrees.

BACKGROUND: We report a genome linkage scan in extended Utah pedigrees, utilizing a pedigree-splitting approach to reduce intra-familial heterogeneity. METHODS: Fifty-nine pedigrees with at least four Prostate cancer (PrCa) cases and no more than two meioses separating PrCa cases were analyzed using the CIDR genomic search STRP marker set. Parametric linkage analyses using dominant and recessive models were performed on four datasets resulting from a pedigree splitting algorithm. In addition, age at diagnosis subset analyses were performed. RESULTS: Four regions of interest (LODs>1.9) were identified on chromosomes 1p, 3q, 5q, and 22q. The linkage peaks on 1p, 3q, and 22q have been previously implicated for PrCa, though not significantly. The 1p region was supported by a single large Utah pedigree with a multipoint LOD score of 3.1. An additional 10 regions gave LOD scores>1.22 (nominal linkage evidence), including moderate evidence supporting the HPC20 region with a recessive model. CONCLUSIONS: Our genome-wide search in the informative, extended Utah pedigrees continues to illustrate an ability to identify and replicate linkage peaks, and supports four regions of interest for PrCa predisposition genes.

Chromosome Mapping↗

PubMed2005

Lobular breast cancer: excess familiality observed in the Utah Population Database.

Family history of breast cancer (BC) is a strong predictor for developing female BC. Whether this excess familiality differs within morphological BC subgroups remains unclear. We assessed the risk of lobular breast cancer (LOB) and any BC among relatives of probands with LOB. We used the Utah Population Database (UPDB) to estimate familial relative risks (FRR) as well as average relatedness, using the genealogical index of familiality (GIF) statistic. The UPDB, a population-based resource, links genealogical data from over 2 million individuals to the Utah Cancer Registry. Consistent with other studies, analysis of all BC cases showed significantly increased risk of BC to relatives (first-degree relative [FDR]: FRR = 1.83, 95% confidence interval [CI] = 1.75-1.90). Morphology-specific risks showed that relatives of LOB probands had an increased risk of LOB (FDR: FRR = 4.51, 95% CI = 2.79-6.89) and an increased risk of any BC (FDR: FRR = 2.47, 95% CI = 2.12-2.85); both measures were significantly greater than the all BC FRR estimates, and surpassed even generalized early-onset BC risk. GIF analyses corroborated the FRR results and indicated that the excess relatedness of LOB cases extended to third-degree relatives. Our findings suggest that LOB has a heritable component and may represent a genetically homogeneous form of BC. Pedigrees with excess LOB may be useful in isolating additional BC predisposition genes. Relatives of women with LOB are at higher risk for BC than relatives of other BC subtypes; a more rigorous BC screening regime may be warranted for these individuals.

Age of Onset↗

PubMed2005

Population-based risk assessment for other cancers in relatives of hereditary prostate cancer (HPC) cases.

BACKGROUND: To identify associations of other cancers with hereditary prostate cancer (HPC) we estimated relative risks (RRs) of 36 different cancers in relatives of prostate cancer cases in the Utah Population Data Base (UPDB), which combines genealogical and cancer data for Utah. METHODS: We utilized known genetic relationships between prostate cancer cases and their relatives with cancer, combined with age- and sex-specific cancer rates calculated internally from the UPDB, to estimate RRs for cancer in relatives of prostate cancer cases. RESULTS: Multiple other cancers were observed in excess in both first- and second-degree relatives of HPC cases including colon cancer, non-Hodgkins lymphoma, multiple myeloma, rectal cancer, cancer of the gallbladder, and melanoma (skin). CONCLUSIONS: This analysis supports the existence of heritable prostate cancer syndromes that include other cancers. We hypothesize that the study of homogeneous pedigrees co-segregating prostate cancer and another cancer could allow more straightforward localization and identification of the gene(s) responsible.

Adult↗

PubMed2005

Characterization of the linkage disequilibrium structure and identification of tagging-SNPs in five DNA repair genes.

BACKGROUND: Characterization of the linkage disequilibrium (LD) structure of candidate genes is the basis for an effective association study of complex diseases such as cancer. In this study, we report the LD and haplotype architecture and tagging-single nucleotide polymorphisms (tSNPs) for five DNA repair genes: ATM, MRE11A, XRCC4, NBS1 and RAD50. METHODS: The genes ATM, MRE11A, and XRCC4 were characterized using a panel of 94 unrelated female subjects (47 breast cancer cases, 47 controls) obtained from high-risk breast cancer families. A similar LD structure and tSNP analysis was performed for NBS1 and RAD50, using publicly available genotyping data. We studied a total of 61 SNPs at an average marker density of 10 kb. Using a matrix decomposition algorithm, based on principal component analysis, we captured >90% of the intragenetic variation for each gene. RESULTS: Our results revealed that three of the five genes did not conform to a haplotype block structure (MRE11A, RAD50 and XRCC4). Instead, the data fit a more flexible LD group paradigm, where SNPs in high LD are not required to be contiguous. Traditional haplotype blocks assume recombination is the only dynamic at work. For ATM, MRE11A and XRCC4 we repeated the analysis in cases and controls separately to determine whether LD structure was consistent across breast cancer cases and controls. No substantial difference in LD structures was found. CONCLUSION: This study suggests that appropriate SNP selection for an association study involving candidate genes should allow for both mutation and recombination, which shape the population-level genomic structure. Furthermore, LD structure characterization in either breast cancer cases or controls appears to be sufficient for future cancer studies utilizing these genes.

Acid Anhydride Hydrolases↗

PubMed2005

A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics.

Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.

Aged↗

PubMed2005

Examination of ELN as a candidate gene in the Utah intracranial aneurysm pedigrees.

BACKGROUND AND PURPOSE: A study of intracranial aneurysm (IA) sibpairs suggested association of an ELN haplotype with IA risk. Subsequent linkage analysis of the ELN region on chromosome 7q11 in high-risk Utah IA pedigrees significantly confirmed linkage between IA and the ELN region. METHODS: We have investigated the ELN gene as a potential candidate gene for IA in Utah pedigrees. One IA case from each pedigree, who shared an ELN region haplotype segregating in the pedigree, was screened for mutation. The promoter region, 34 exons, and the 3'UTR (UnTranslated Region) of the ELN gene were screened for variants using DHPLC. RESULTS: Variants were observed in the promoter region, exons 4 and 6, and the 3'UTR. Variants in exon 6 and in one 3'UTR position were unique to Utah. The remaining variants were absent in the controls. There was no evidence for segregation of the ELN variants found in IA cases with the hypothesized chromosome 7 haplotypes segregating in pedigrees. CONCLUSIONS: Our analysis does not support ELN as the gene responsible for familial IA in the linked Utah IA pedigrees.

3' Untranslated Regions↗

PubMed2005

Genome-wide linkage analyses of extended Utah pedigrees identifies loci that influence recurrent, early-onset major depression and anxiety disorders.

Major depressive disorder (MDD) is a common, clinically heterogeneous disorder often found comorbid with other disorders. We studied recurrent, early-onset MDD (MDD-RE) and anxiety disorders in combination to define powerful phenotypes for genetic study. We used 87 large, extended Utah pedigrees to investigate linkage to 3 phenotypes: "MDD-RE;" "MDD-RE or anxiety;" and "MDD-RE and anxiety;" where in the latter definition the disorders must appear comorbid within an individual. Pedigrees ranged in size from 2 to 6 generations and contained 3 to 42 individuals affected with MDD or anxiety (718 total). In primary analyses, we identified three regions with at least suggestive genome-wide evidence for linkage on chromosomes 3centr, 7p, and 18q. Both 7p and 18q are replication findings for related phenotypes. The best linkage evidence was for a novel locus at 3p12.3-q12.3 (LOD = 3.88, "MDD-RE or anxiety") and 18q21.33-q22.2 (LOD = 3.75, "MDD-RE and anxiety"), a well-established susceptibility locus for bipolar disorder. In our secondary sex-specific analyses, we identified two further regions of interest on chromosomes 4q and 15q. Using linked pedigrees, we localized 3centr and 18q to 9.8 and 12.2 cM, respectively, with potential for further localization with the addition of markers in specific pedigrees. Our success in replication and novel locus identification illustrates the utility of large extended pedigrees for common disorders, such as MDD. Further, it supports the hypothesis that MDD and anxiety disorders have over-lapping genetic etiologies and suggests that comorbid diagnoses may be useful in defining more genetically homogeneous forms of MDD for linkage mapping.

Anxiety Disorders↗

PubMed2005

Characterization of linkage disequilibrium structure, mutation history, and tagging SNPs, and their use in association analyses: ELAC2 and familial early-onset prostate cancer.

In association analyses, it is critical that informative single-nucleotide polymorphisms (SNPs) be selected for study and utilized appropriately. We sequenced 38 kb, including exons of ELAC2, promoter region and conserved upstream intergenic sequences. A comprehensive characterization of linkage disequilibrium (LD) structure and mutation history was performed using our principal components analysis (PCA) method and a phylogenetic analysis. We identified a complex pattern of LD structure consistent with the occurrence of both recombination and mutation events within ELAC2. Four overlapping and noncontiguous LD groups were defined. Eight tagging SNPs (tSNPs) were identified, accounting for over 90% of the genetic variation of the 19 total variants. We tested associations between familial early-onset prostate cancer (PRCA) and each variant independently and in haplotypes. We performed these tests using all 19 variants and the 8 tSNPs; the results using tSNP haplotypes accurately represent the association evidence for the full haplotypes. We observed increased evidence for association when SNPs were analyzed in haplotypes. The phylogenetic analysis indicated three haplotypes, clustered farthest from the root-node, all of which were found more often in cases than controls. These three haplotypes together showed the best evidence of association with familial, early-onset PRCA (P=0.0024; odds ratio=2.23; 95% CI, 1.33-3.74), indicating possible allelic heterogeneity. Our results suggest that 8 tSNPs are required to comprehensively assess associations in ELAC2, and that haplotypes should be considered for analysis, and that a knowledge of mutation history may be helpful in parsing allelic heterogeneity and suggesting combinations of haplotypes to be tested.

Aged↗

PubMed2005

Dissecting the genetic etiology of major depressive disorder using linkage analysis.

Major depressive disorder (MDD) is clinically and genetically heterogeneous. Studies suggest that recurrence, early onset and comorbid phenotypes define more genetically homogeneous sub-samples. The concordance of linkage findings in recent studies using such approaches is encouraging. Sex-specific analyses and broader phenotypes have also yielded interesting results. These findings indicate that future research should consider comorbid disorders and sex-specific analyses. However, this direction must be approached with caution, owing to the complex multiple-testing issues that arise when considering numerous related phenotypes. With appropriate interpretation, these findings indicate a new potential for positional cloning efforts to locate genes in consensus regions. Genes found might influence specific subtypes of MDD or broader phenotypes, leading to enhanced clinical characterization and management of MDD.

Comorbidity↗