Objective The aim of this study is to discover common variants in 6 lipid metabolic genes and construct and validate a genetic risk score (GRS) based on the joint effects of genetic variants in ...multiple genes from lipid and other pathobiologic pathways. Background Explaining the genetic basis of coronary artery disease (CAD) is incomplete. Discovery and aggregation of genetic variants from multiple pathways may advance this objective. Methods Premature CAD cases (n = 1,947) and CAD-free controls (n = 1,036) were selected from our angiographic registry. In a discovery phase, single nucleotide polymorphisms (SNPs) at 56 loci from internal discovery and external reports were tested for associations with biomarkers and CAD: 28 promising SNPs were then tested jointly for CAD associations, and a GRS consisting of SNPs contributing independently was constructed and validated in a replication set of familial cases and population-based controls (n = 1,320). Results Five variants contributed jointly to CAD prediction in a multigenic GRS model: odds ratio 1.24 (95% CI 1.16-1.33) per risk allele, P = 8.2 × 10−11 , adjusted OR 2.03 (1.53-2.70), fourth versus first quartile. 5-SNP genetic risk score had minor impact on area under the receiver operating characteristic curve ( P > .05) but resulted in substantial net reclassification improvement: 0.16 overall, 0.28 in intermediate-risk patients (both P < .0001). GRS5 predicted familial CAD with similar magnitude in the validation set. Conclusions The Intermountain Healthcare's Coronary Genetics study demonstrates the ability of a multigenic, multipathway GRS to improve discrimination of angiographic CAD. Genetic risk scores promise to increase understanding of the genetic basis of CAD and improve identification of individuals at increased CAD risk.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Single nucleotide polymorphisms (SNPs) in matrix metalloproteinase (MMP) genes may be associated with myocardial infarction (MI) and coronary artery disease (CAD), but studies of multiple ...MMP genes and their tissue inhibitors (TIMPs) are scarce. Furthermore, differentiation of predictive ability by end point (MI vs CAD) has not been addressed. This study evaluated the association with MI of SNPs in genes encoding MMPs 1, 2, 3, and 9 and TIMPs 1, 2, and 3. Methods Genotypes of patients (N = 5148) with MI (n = 1693) and angiographically defined CAD (≥1 lesion of ≥70% stenosis, n = 1967) were compared with MI-free (n = 3455) and non-CAD patients (n = 1122), respectively. Because of linkage disequilibrium, MMP-1 and MMP-3 SNPs (chromosome 11) were combined, as were the 2 MMP-9 SNPs. Results For MI, only MMP-9 group CT/RQ (odds ratio OR 1.25, P = .007 vs wild-type CC/RR) had greater MI risk, with TT/QQ having a weak trend (OR 1.43, P = .10). These findings remained (CT/RQ) or were strengthened (TT/QQ) after full adjustment. For CAD, association was found for MMP-1/MMP-3 groups 2G1G/6A6A (OR 1.45, P = .022), 2G1G/6A5A (OR = 1.49, P = .001), 2G1G/5A5A (OR 1.64, P = .003), and 1G1G/5A5A (OR 1.35, P = .035) compared to wild type. Conclusions Composite MMP-9 genotypes but not other SNPs were associated with MI, whereas MMP-1/MMP-3 genotypes were CAD-associated. The largest MMP/TIMP gene study to date, this study suggests care in selection and definition of clinical phenotypes. Furthermore, this suggests that the evaluated SNPs only approximately account for intragenic variation in these genes and that comprehensive evaluation of all variations in these genes should better elucidate associations with MI and CAD phenotypes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Major depression disorder is a common psychiatric disease with a major economic impact on society. In many cases, no effective treatment is available. The etiology of major depression is complex, but ...it is clear that the disease is, to a large extent, determined genetically, especially among individuals with a familial history of major depression, presumably through the involvement of multiple predisposition genes in addition to an environmental component. As a first step toward identification of chromosomal loci contributing to genetic predisposition to major depression, we have conducted a genomewide scan by using 628 microsatellite markers on 1,890 individuals from 110 Utah pedigrees with a strong family history of major depression. We identified significant linkage to major depression in males at marker D12S1300 (multipoint heterogeneity LOD score 4.6;
P=.00003 after adjustment for multiple testing). With additional markers, the linkage evidence became highly significant, with the multipoint heterogeneity LOD score at marker D12S1706 increasing to 6.1 (
P=.0000007 after adjustment for multiple testing). This study confirms the presence of one or more genes involved in psychiatric diseases on the q arm of chromosome 12 and provides strong evidence for the existence of a sex-specific predisposition gene to major depression at 12q22-q23.2.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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).
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
High-risk pedigrees (
) are a powerful design to map highly penetrant risk genes. We previously described Shared Genomic Segment (SGS) analysis, a mapping method for single large extended pedigrees ...that also addresses genetic heterogeneity inherent in complex diseases. SGS identifies shared segregating chromosomal regions that may inherit in only a subset of cases. However, single large pedigrees that are individually powerful (at least 15 meioses between studied cases) are scarce. Here, we expand the SGS strategy to incorporate evidence from two extended HRPs by identifying the same segregating risk locus in both pedigrees and allowing for some relaxation in the size of each HRP.
Duo-SGS is a procedure to combine single-pedigree SGS evidence. It implements statistically rigorous duo-pedigree thresholding to determine genome-wide significance levels that account for optimization across pedigree pairs. Single-pedigree SGS identifies optimal segments shared by case subsets at each locus across the genome, with nominal significance assessed empirically. Duo-SGS combines the statistical evidence for SGS segments at the same genomic location in two pedigrees using Fisher's method. One pedigree is paired with all others and the best duo-SGS evidence at each locus across the genome is established. Genome-wide significance thresholds are determined through distribution-fitting and the Theory of Large Deviations. We applied the duoSGS strategy to eleven extended, myeloma HRPs.
We identified one genome-wide significant region at 18q21.33 (0.85 Mb,
= 7.3 × 10
) which contains one gene,
. Thirteen regions were genome-wide suggestive: 1q42.2, 2p16.1, 3p25.2, 5q21.3, 5q31.1, 6q16.1, 6q26, 7q11.23, 12q24.31, 13q13.3, 18p11.22, 18q22.3 and 19p13.12.
Our results provide novel risk loci with segregating evidence from multiple HRPs and offer compelling targets and specific segment carriers to focus a future search for functional variants involved in inherited risk formyeloma.
Genomewide association studies have resulted in a great many genomic regions that are likely to harbor disease genes. Thorough interrogation of these specific regions is the logical next step, ...including regional haplotype studies to identify risk haplotypes upon which the underlying critical variants lie. Pedigrees ascertained for disease can be powerful for genetic analysis due to the cases being enriched for genetic disease. Here we present a Monte Carlo based method to perform haplotype association analysis. Our method, hapMC, allows for the analysis of full-length and sub-haplotypes, including imputation of missing data, in resources of nuclear families, general pedigrees, case-control data or mixtures thereof. Both traditional association statistics and transmission/disequilibrium statistics can be performed. The method includes a phasing algorithm that can be used in large pedigrees and optional use of pseudocontrols.
Our new phasing algorithm substantially outperformed the standard expectation-maximization algorithm that is ignorant of pedigree structure, and hence is preferable for resources that include pedigree structure. Through simulation we show that our Monte Carlo procedure maintains the correct type 1 error rates for all resource types. Power comparisons suggest that transmission-disequilibrium statistics are superior for performing association in resources of only nuclear families. For mixed structure resources, however, the newly implemented pseudocontrol approach appears to be the best choice. Results also indicated the value of large high-risk pedigrees for association analysis, which, in the simulations considered, were comparable in power to case-control resources of the same sample size.
We propose hapMC as a valuable new tool to perform haplotype association analyses, particularly for resources of mixed structure. The availability of meta-association and haplotype-mining modules in our suite of Monte Carlo haplotype procedures adds further value to the approach.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PedGenie software, introduced in 2006, includes genetic association testing of cases and controls that may be independent or related (nuclear families or extended pedigrees) or mixtures thereof using ...Monte Carlo significance testing. Our aim is to demonstrate that PedGenie, a unique and flexible analysis tool freely available in Genie 2.4 software, is significantly enhanced by incorporating meta statistics for detecting genetic association with disease using data across multiple study groups.
Meta statistics (chi-squared tests, odds ratios, and confidence intervals) were calculated using formal Cochran-Mantel-Haenszel techniques. Simulated data from unrelated individuals and individuals in families were used to illustrate meta tests and their empirically-derived p-values and confidence intervals are accurate, precise, and for independent designs match those provided by standard statistical software.
PedGenie yields accurate Monte Carlo p-values for meta analysis of data across multiple studies, based on validation testing using pedigree, nuclear family, and case-control data simulated under both the null and alternative hypotheses of a genotype-phenotype association.
PedGenie allows valid combined analysis of data from mixtures of pedigree-based and case-control resources. Added meta capabilities provide new avenues for association analysis, including pedigree resources from large consortia and multi-center studies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Polymorphisms in DNA double-strand break repair gene XRCC2 may play an important role in colorectal cancer etiology, specifically in disease subtypes. Associations of XRCC2 variants and colorectal ...cancer were investigated by tumor site and tumor instability status in a four-center collaboration
including three U.K. case-control studies (Sheffield, Leeds, and Dundee) and a U.S. case-control study of cases from high-risk
Utah pedigrees (total: 1,252 cases and 1,422 controls). The 14 variants studied were tagging single nucleotide polymorphisms
(SNP) selected from National Institute of Environmental Health Sciences/HapMap data supplemented with SNPs identified from
sequencing of 125 cases chosen to represent multiple colorectal cancer groups (familial, metastatic disease, and tumor subsite).
Monte Carlo significance testing using Genie software provided valid meta-analyses of the total resource that includes family-based
data. Similar to reports of colorectal cancer and other cancer sites, the rs3218536 R188H allele was not associated with increased
risk. However, we observed a novel, highly significant association of a common SNP, rs3218499G>C, with increased risk of rectal
tumors (odds ratio, 2.1; 95% confidence interval, 1.3-3.3; P χ 2 = 0.0006) versus controls, with the largest risk found for female rectal cases (odds ratio, 3.1; 95% confidence interval,
1.6-6.1; P χ 2 = 0.0006). This difference was significantly different to that for proximal and distal colon cancers ( P χ 2 = 0.02). Our investigation supports a role for XRCC2 in colorectal cancer tumorigenesis, conferring susceptibility to rectal tumors. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2476–84)
We applied a shared genomic segment (SGS) analysis, incorporating an error model, to identify complete, or near complete, selective sweeps in the HapMap phase II data sets. This method is based on ...detecting heterozygous sharing across all individuals within a population, to identify regions of sharing with at least one allele in common. We identified multiple interesting regions, many of which are concordant with positive selection regions detected by previous population genetic tests. Others are suggested to be novel regions. Our finding illustrates the utility of SGS as a method for identifying regions of selection, and some of these regions have been proposed to be candidate regions for harboring disease genes.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objectives
Gastroschisis remains an etiologic dilemma. We posit that an underlying genetic susceptibility either separately or coupled with a periconceptional environmental exposure stimulates an ...inflammatory response resulting in gastroschisis. To investigate the genetic link, we applied shared genomic segment (SGS) analysis, a novel approach to discover chromosomal segments that inherit in high‐risk multigenerational pedigrees.
Methods
We studied pedigrees containing distantly related children with gastroschisis originating from a common ancestor. We used the Illumina OmniExpress genotyping array with >700,000 SNPs. Samples from 40 affected children in 13 pedigrees (≥3 affected children) were genotyped to generate the high‐density SNP data necessary to perform SGS analysis. Assessment of significance in SGS was determined empirically using simulations based on precise pedigree structure and modeling linkage disequilibrium (LD) for SNPs in the general population to properly account for genetic architecture. The LD model was estimated from the 1000 Genome Project using the same set of SNPs. Genome‐wide significance thresholds were determined for each pedigree.
Results
We identified six pedigrees that contained genome‐wide statistically significant SGS regions inherited from a common founder. These regions were different in each pedigree, all contained immune pathway genes.
Discussion
The genome‐wide significant regions support a genetic susceptibility for gastroschisis. The regions are compelling candidates for regionally focused genome sequencing, enabling the discovery of coding or noncoding (e.g., regulatory) risk variants, the latter of which are unlikely to be found using conventional exomic/gene‐focused approaches. This technique provides a comprehensive and focused genomic interrogation that will help to advance our understanding of gastroschisis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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