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PubMed2006

Multiple association analysis via simulated annealing (MASSA).

SUMMARY: Genome-wide association studies are now technically feasible and likely to become a fundamental tool in unraveling the ultimate genetic basis of complex traits. However, new statistical and computational methods need to be developed to extract the maximum information in a realistic computing time. Here we propose a new method for multiple association analysis via simulated annealing that allows for epistasis and any number of markers. It consists of finding the model with lowest Bayesian information criterion using simulated annealing. The data are described by means of a mixed model and new alternative models are proposed using a set of rules, e.g. new sites can be added (or deleted), or new epistatic interactions can be included between existing genetic factors. The method is illustrated with simulated and real data. AVAILABILITY: An executable version of the program (MASSA) running under the Linux OS is freely available, together with documentation, at http://www.icrea.es/pag.asp?id=Miguel.Perez.

Algorithms↗
PubMed2006

P2BAT: a massive parallel implementation of PBAT for genome-wide association studies in R.

UNLABELLED: The software tool P2BAT provides a massive parallel and user friendly implementation of the PBAT-analysis tools for family-based association tests (FBATs) in large-scale studies, including genome-wide association studies with several thousand subjects. Built on the original PBAT-implementation of the Lange-Van Steen algorithm to bypass the multiple testing problem in family-based association studies, P2BAT integrates all PBAT-analysis tools for binary and complex traits into R and makes them accessible through a user-friendly GUI. The genome-wide analysis tools are fully automated and can be ran massively parallel directly through the GUI. P2BAT is fully documented and contains graphical output tools for time-to-onset analysis. P2BAT also features the ability to test for gene and environment/drug interaction. AVAILABILITY: The P2BAT package is available as the R package 'pbatR' which can be downloaded from http://cran.r-project.org/. The PBAT-software is available at http://www.biostat.harvard.edu/~clange/.

Algorithms↗
PubMed2006

SNiPer-HD: improved genotype calling accuracy by an expectation-maximization algorithm for high-density SNP arrays.

MOTIVATION: The technology to genotype single nucleotide polymorphisms (SNPs) at extremely high densities provides for hypothesis-free genome-wide scans for common polymorphisms associated with complex disease. However, we find that some errors introduced by commonly employed genotyping algorithms may lead to inflation of false associations between markers and phenotype. RESULTS: We have developed a novel SNP genotype calling program, SNiPer-High Density (SNiPer-HD), for highly accurate genotype calling across hundreds of thousands of SNPs. The program employs an expectation-maximization (EM) algorithm with parameters based on a training sample set. The algorithm choice allows for highly accurate genotyping for most SNPs. Also, we introduce a quality control metric for each assayed SNP, such that poor-behaving SNPs can be filtered using a metric correlating to genotype class separation in the calling algorithm. SNiPer-HD is superior to the standard dynamic modeling algorithm and is complementary and non-redundant to other algorithms, such as BRLMM. Implementing multiple algorithms together may provide highly accurate genotyping calls, without inflation of false positives due to systematically miss-called SNPs. A reliable and accurate set of SNP genotypes for increasingly dense panels will eliminate some false association signals and false negative signals, allowing for rapid identification of disease susceptibility loci for complex traits. AVAILABILITY: SNiPer-HD is available at TGen's website: http://www.tgen.org/neurogenomics/data.

Algorithms↗
PubMed2006

Linkage analysis using sex-specific recombination fractions with GENEHUNTER-MODSCORE.

MOTIVATION: Sex-specific marker maps have become increasingly available. We have implemented the usage of sex-specific recombination frequencies in the GENEHUNTER-MODSCORE program that performs multipoint linkage analysis. Furthermore, we have devised a consistent method to choose the combinations of male and female genetic positions at which linkage scores should be calculated. Marker coordinates can be read automatically from publicly available genetic maps. RESULTS: In a MOD-score analysis of the COGA dataset provided for Genetic Analysis Workshop 14, the highest linkage peak on chromosome 1 further increases when using sex-specific maps, while some smaller peaks are decreased. Simulations confirm that the MOD score can be biased when a sex-averaged instead of the correct sex-specific map is employed. This shows that an adequate modeling of the female:male ratio of genetic distances is important, especially for complex traits. AVAILABILITY: The new version of GENEHUNTER-MODSCORE can be downloaded from the following website: http://www.staff.uni-marburg.de/~strauchk/software.html

Algorithms↗
PubMed2003

Identification of two keratinocyte stem cell regulatory loci implicated in skin carcinogenesis.

Several converging lines of evidence suggest that keratinocyte stem cells including those clonogenic in vitro, are the target cells in skin carcinogenesis. However, the mechanism of their involvement in carcinogenesis continues to be unknown. Recently, we have demonstrated that the number of keratinocyte clonogenic stem cells from mice is a genetically defined and quantitative complex trait. In this study, we analyzed the size of the colonies in BALB/c, C57BL/6, and their (BALB/cxC57BL/6)F1 hybrid mice. We found that the size of the colonies is also genetically regulated and that there are at least two types of clonogenic keratinocytes that form either small or large colonies. Small and large colony numbers were significantly different in BALB/c and C57BL/6 mice. We performed a genome-wide scan of small and large colony number in the two backcrosses [BALB/cx (BALB/cxC57BL/6)F1]; [C57BL/6x (BALB/cxC57BL/6) F1]; and [(BALB/cxC57BL/6)F1x (BALB/cxC57BL/6)F1] intercross mice. We report here that the loci on chromosomes 4 and 9 play a role in the regulation of large and small colony number respectively. We conclude that mouse epidermis has two major types of stem cells generating small and large colonies, and regulated by different genes. Our results suggest that the loci, including one major and several minor loci linked to the subpopulation of keratinocytes forming small colonies were related, if not identical to, the loci linked to susceptibility or resistance to skin tumor promotion and skin tumor development.

Animals↗
PubMed2007

The common non-synonymous variant G38S of the KCNE1-(minK)-gene is not associated to QT interval in Central European Caucasians: results from the KORA study.

AIMS: The QT interval in the general population is a complex trait with 30-50% heritability. QT prolongation is associated with an increased risk of sudden death. A recent family-based study found an association between QT interval and the common non-synonymous Glycin 38 Serine variant (G38S, rs1805127) of the KCNE1 gene coding for the minK-potassium channel subunit. We intended to replicate this finding in a large population sample of central European Caucasian ancestry as part of our ongoing search for genetic variants predisposing to arrhythmias. METHODS AND RESULTS: We studied 3966 unrelated individuals from the KORA S4 population-based study without atrial fibrillation, pacemaker implant, or pregnancy. Individuals were genotyped by MALDI-TOF mass spectrometry. We did not detect any significant association between the genotypes of the G38S variant and the QT interval in the entire population or in any gender. CONCLUSION: Unlike the common Lysine 897 Threonine variant of KCNH2 (K897T, rs1805123) the G38S variant of KCNE1 does not appear to have a strong modifying effect on QT interval. However, we cannot rule out an effect of G38S on QT in other ethnic groups, under exercise or medications or on the risk for arrhythmias and sudden death.

Adult↗
PubMed1997

Altering developmental trajectories in mice by restricted index selection.

A restricted index selection experiment on mice was carried out for 1-4 generations on rate of early postnatal development (growth rate from birth to 10 days of age) vs. rate of development much later in ontogeny (growth rate from 28 to 56 days of age). Early rate of development (E) approximates hyperplasia (changes in cell number) and later rate (L) reflects hypertropy (changes in cell size). The selection criteria were as follows; E+LO was selected to increase early body weight gain while holding late body weight gain constant; E-LO was selected to decrease early body gain while holding late gain constant; EOL+ was selected to increase late gain holding early gain constant; and EOL- was selected to decrease late gain holding early gain constant. After 14 generations of selection, significant divergence among lines has occurred and the changes in the growth trajectories are very close to expectation. The genetic and developmental bases of complex traits are discussed as well as the concept of developmental homoplasy.

Animals↗
PubMed2001

Joint linkage and linkage disequilibrium mapping in natural populations.

A new strategy for studying the genome structure and organization of natural populations is proposed on the basis of a combined analysis of linkage and linkage disequilibrium using known polymorphic markers. This strategy exploits a random sample drawn from a panmictic natural population and the open-pollinated progeny of the sample. It is established on the principle of gene transmission from the parental to progeny generation during which the linkage between different markers is broken down due to meiotic recombination. The strategy has power to simultaneously capture the information about the linkage of the markers (as measured by recombination fraction) and the degree of their linkage disequilibrium created at a historic time. Simulation studies indicate that the statistical method implemented by the Fisher-scoring algorithm can provide accurate and precise estimates for the allele frequencies, recombination fractions, and linkage disequilibria between different markers. The strategy has great implications for constructing a dense linkage disequilibrium map that can facilitate the identification and positional cloning of the genes underlying both simple and complex traits.

Alleles↗
PubMed2003

Power evaluations for family-based tests of association with incomplete parental genotypes.

While a variety of methods have been developed to deal with incomplete parental genotype information in family-based association tests, sampling design issues with incomplete parental genotype data still have not received much attention. In this article, we present simulation studies with four genetic models and various sampling designs and evaluate power in family-based association studies. Efficiency depends heavily on disease prevalence. With rare diseases, sampling affecteds and their parents is preferred, and three sibs will be required to have close power if parents are unavailable. With more common diseases, sampling affecteds and two sibs will generally be more efficient than trios. When parents are unavailable, siblings need not be phenotyped if the disease is rare, but a loss of power will result with common diseases. Finally, for a class of complex traits where other genetic and environmental factors also cause phenotypic correlation among siblings, little loss of efficiency occurs to rare disease, but substantial loss of efficiency occurs to common disease.

Data Interpretation, Statistical↗
PubMed2003

Sequences associated with human iris pigmentation.

To determine whether and how common polymorphisms are associated with natural distributions of iris colors, we surveyed 851 individuals of mainly European descent at 335 SNP loci in 13 pigmentation genes and 419 other SNPs distributed throughout the genome and known or thought to be informative for certain elements of population structure. We identified numerous SNPs, haplotypes, and diplotypes (diploid pairs of haplotypes) within the OCA2, MYO5A, TYRP1, AIM, DCT, and TYR genes and the CYP1A2-15q22-ter, CYP1B1-2p21, CYP2C8-10q23, CYP2C9-10q24, and MAOA-Xp11.4 regions as significantly associated with iris colors. Half of the associated SNPs were located on chromosome 15, which corresponds with results that others have previously obtained from linkage analysis. We identified 5 additional genes (ASIP, MC1R, POMC, and SILV) and one additional region (GSTT2-22q11.23) with haplotype and/or diplotypes, but not individual SNP alleles associated with iris colors. For most of the genes, multilocus gene-wise genotype sequences were more strongly associated with iris colors than were haplotypes or SNP alleles. Diplotypes for these genes explain 15% of iris color variation. Apart from representing the first comprehensive candidate gene study for variable iris pigmentation and constituting a first step toward developing a classification model for the inference of iris color from DNA, our results suggest that cryptic population structure might serve as a leverage tool for complex trait gene mapping if genomes are screened with the appropriate ancestry informative markers.

Chromosomes, Human, Pair 10↗
PubMed1972

Laboratory studies bearing on pigment pattern polymorphisms in wild populations of Rana pipiens.

Data are presented for 2,393 progeny from a number of crosses related to a study in ecological genetics of the Burnsi and Kandiyohi polymorphisms in natural populations of the leopard frog, Rana pipiens. No significant differences in viability were found between wild-type homozygotes (+/+) and Burnsi heterozygotes (B/+) or homozygotes (B/B). Similarly, no difference in viability was found between wild-type (+/+) and Kandiyohi heterozygotes (K/+) and homozygotes (K/K). However, there appears to be slight reduction in viability of the double dominant heterozygote (B/+; K/+) in comparison with (+/+), (B/+), and (K/+) progeny from the same cross.-The Kandiyohi heterozygotes (K/+) appeared to have a more rapid rate of development from fertilization through metamorphosis than wild-type (+/+) or Burnsi (B+/) or Burnsi-Kandiyohi heterozygotes (B+K/+). Since Kandiyohi is associated primarily with the prairie habitat (Merrell 1965), this finding suggests that the adaptive advantage of Kandiyohi lies in the more rapid rate of development of frogs carrying this gene, enabling them to complete metamorphosis before the prairie breeding ponds dry up.-Data are presented from crosses involving dorsal spot number. The results suggest that heredity plays a role in the determination of dorsal spot number but that non-genetic influences are also of considerable importance.-The results of these crosses are discussed with respect to their bearing on the formation of pigment patterns in Rana pipiens. From the available data it is clear that the pigment pattern in Rana pipiens is a complex trait influenced by major gene loci, by modifying genes, and by environmental effects. The relative importance of these factors varies depending on the particular combination of genetic and environmental conditions.

Adaptation, Biological↗
PubMed1997

Determinants of bone mineral density in postmenopausal white Iowans.

BACKGROUND: Osteoporosis is a major health problem for older individuals. For women, development of osteoporosis is a function of the accretion of "peak" bone mass in the third decade, age at menopause, and rate of bone loss with aging. Low bone mineral density (BMD) is a major risk factor for osteoporosis and fracture. The purpose of this study was to identify life style, nutritional, medical, and genetic predictors of low BMD in postmenopausal Iowa women. METHODS: One hundred thirty-four postmenopausal White women ranging in age from 57 to 81 years were included in this case-control study. Bone mineral density was measured at the femoral neck, using dual photon X-ray absorptiometry (Hologic 2000 QDR). Sixty-six women with BMD measurements below 0.68 g/cm2 (the bottom quartile of the BMD distribution in the population from which participants were recruited), and 68 women with values at or above 0.83 g/cm2 (the top quartile of the BMD distribution in the same population) were included. Information about environmental, nutritional, medical, and life style modifiers of BMD was obtained by written questionnaire and telephone interview. To assess familial factors that might influence BMD, we obtained a detailed family history for each participant. In addition, we tested the hypothesis that allelic variation at the Vitamin D receptor (VDR), and the type I collagen gene (COL1A1 and COL1A2) loci influence BMD. RESULTS: Weight, loss of height, age, and age at menopause were strong predictors of BMD in our population. After adjustment for these differences, we found no effect of genotype at the COL1A1, COL1A2, and VDR loci on BMD. CONCLUSIONS: Bone mineral density is a complex trait that is influenced by several different modifiers; in the present study, weight was the best predictor of postmenopausal BMD. While several studies suggest that VDR genotype is an important determinant of BMD, we did not find this association in our population, nor did we identify an association between allelic variation at the type I collagen gene loci and BMD. Identification of genes that determine body mass index may provide additional insight into risk factors for low BMD, and osteoporotic fractures.

Aged↗
PubMed2001

Long-range sequence composition mirrors linkage disequilibrium pattern in a 1.13 Mb region of human chromosome 22.

Association studies, the most powerful tool for the identification of genes underlying complex traits, depend on the observation of linkage disequilibrium (LD) between marker alleles and the trait. The LD pattern of the human genome which determines the regional density of required markers is non-uniform, with regions of long-range LD over several hundred kilobases and regions where LD extends only over a few kilobases. Studying LD in the NF1 gene region we encountered a transition from long-range to short-range LD which coincides with a switch in the isochore pattern. This observation prompted us to investigate the regional variation in the extent of LD more systematically and we selected an isochore transition within the MN1/PITPNB gene region on chromosome 22q12.1. Long-range LD characterizes the GC-poor (40% GC) parts of the sequences. No LD can be observed between closely spaced markers throughout the whole range of the GC-rich (50% GC) parts. In both cases, the NF1 and the MN1/PITPNB gene region, a clear-cut transition of the long-range GC content precisely coincides with a change in the extent of observable LD. The results can be explained by a 72-fold lower recombination frequency in the GC-poor, compared to the GC-rich isochores. Although recombination is not the only factor governing LD, our findings can help to predict levels of LD and marker densities required for association studies on the basis of regional GC content.

Base Composition↗
PubMed2001

The genome-wide distribution of background linkage disequilibrium in a population isolate.

Recent interest in using association studies to investigate complex traits has focused attention on understanding linkage disequilibrium (LD) in the human genome. We examined the genome-wide distribution and magnitude of such background LD (BLD) using 1036 densely spaced microsatellites, in a sample from the demographically well characterized population of the Central Valley of Costa Rica. High levels of BLD were found between linked markers several centiMorgans apart, and although BLD was significantly related to genetic distance between markers it was not spread uniformly throughout the genome. Understanding the forces governing the distribution of BLD in the genome will require similar investigations using a standard set of markers in other populations.

Genetic Markers↗
PubMed2001

Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci.

Type 1 diabetes mellitus is a common disease with a complex mode of inheritance. Its aetiology is underpinned by a major locus, insulin-dependent diabetes mellitus 1 (IDDM1) in the human leukocyte antigen (HLA) region of chromosome 6p21, and an unknown number of loci of lesser individual effect. In linkage analyses IDDM1 is a single peak, but it is evident that the linkage is caused by allelic variation of three adjacent genes in a 75 kb region, namely the class II genes, HLA-DRB1, -DQA1 and -DQB1. However, even these three genes may not explain all of the HLA association. We investigated, in the founder population of Sardinia, whether non-DQ/DR polymorphic markers within a 9.452 Mb region encompassing the whole HLA complex further influence the disease risk, after taking into account linkage disequilibrium with the disease loci HLA-DQB1, -DQA1 and -DRB1. We generalized the conditional association test, the haplotype method, to detect marker associations that are independent of the main DR/DQ disease associations. Three regions were identified as risk modifiers. These associations were not only independent of the polymorphic exon 2 sequences of HLA-DQB1, -DQA1 and -DRB1, but also independent of each other. The individual contributions of these risk modifiers were relatively modest but their combined impact was highly significant. Together, alleles of single nucleotide polymorphisms at the DMB and DOB genes, and the microsatellite locus TNFc, identified approximately 40% of Sardinian DR3 haplotypes as non-predisposing. This conditional analysis approach can be applied to any chromosome region involved in the predisposition to complex traits.

Chromosome Mapping↗
PubMed2002

Evidence for an inflammatory bowel disease locus on chromosome 3p26: linkage, transmission/disequilibrium and partitioning of linkage.

Crohn's disease and ulcerative colitis, the two major forms of idiopathic inflammatory bowel disease (IBD), are heritable, complex traits that appear to share some but not all susceptibility loci. We report that transmission/disequilibrium test analysis of a Crohn's disease genome scan dataset has detected an inflammatory bowel disease locus on chromosome 3p26 (nominal P=0.000052 and genome-wide corrected P=0.039 at D3S1297). An allele sharing method shows significant linkage (multipoint lod=3.69) in a larger, independent sample of inflammatory bowel disease-affected sibling pairs. A survey of 16 chromosome 3p26 short tandem repeat polymorphisms in a combined sample of 234 independent nuclear families with 324 IBD-affected sibling pairs shows significant linkage to chromosome 3p26 (multipoint lod=3.78) and significant transmission/disequilibrium test results at two adjacent markers (nominal P values in two different transmission/disequilibrium analysis methods=0.00011 and 0.0011 for the first marker, and 0.00071 and 0.00013 for the second marker). There is highly significant under-transmission of a common allele and modest over-transmission of other alleles at both markers. Families with no transmission to affected individuals of the under-transmitted alleles show significant linkage (multipoint lod=4.50) that is significantly greater in four simulation studies (P=0.0001, 0.0000625, 0.0000625 and 0.0000625, respectively) than the linkage evidence in families with transmission of the under-transmitted alleles (multipoint lod=0.12). Thus, the existence of an inflammatory bowel disease locus on chromosome 3p26 is supported by significant linkage, transmission/disequilibrium and partitioning of linkage evidence.

Chromosome Mapping↗
PubMed1999

Crooked tail (Cd) models human folate-responsive neural tube defects.

Genetic correlation of human neural tube defects (NTDs) with NTD genes identified in mouse may unravel predisposing complex traits for assessment of individual risk and treatment in clinical settings. Folic acid (FA) can reduce the recurrence of NTDs in human populations by as much as 50-70%, though the mechanism of this rescue is unknown. We examined whether Crooked tail ( Cd ), a mouse strain prone to exencephaly, could provide a genetic animal model for folate-responsive NTDs. The Cd locus was localized to a 0.2 cM interval of the Mouse Genome Database genetic map, identifying tightly linked markers for genotyping prior to phenotypic expression. In a controlled diet study, Cd was found to mimic closely the clinical response to FA. FA supplementation reduced the recurrence risk of Cd exencephaly by as much as 55%. This rescue was dose dependent and did not require subjects to be inherently folate deficient. Like the female predominance of NTDs in humans, female Cd embryos were most likely to display exencephaly and were more responsive than males to the FA rescue. Importantly, FA supplementation shifted the severity of Cd phenotypic expression from early embryonic lethality to longer survival, and reduced the incidence of NTDs. The Cd locus is distinct from the known genes associated with neurulation defects, and isolation of this gene will assist identification of biochemical, genetic and gender-dependent factors contributing to folate-responsive NTDs.

Animals↗
PubMed2003

Linkage disequilibrium patterns of the human genome across populations.

We studied the patterns of linkage disequilibrium (LD) in the human genome among three populations: African Americans, Caucasians and Ashkenazi Jews. These three populations represent admixed, outbred and isolated populations, respectively. The study examined defined chromosomal regions across the whole genome. We found that SNP allele frequencies are highly correlated between Ashkenazi Jews and Caucasians and somewhat distinct in African Americans. In addition, Ashkenazi Jews have a modest increase in LD compared with Caucasians, and both have greater LD than African Americans. The three populations differed more significantly with regard to haplotype heterogeneity. We found, as expected, that Ashkenazi Jews display the greatest extent of homogeneity and African Americans the greatest extent of heterogeneity. We found that most of the variance in LD can be attributed to the difference between regions and markers rather than to that between different population types. The average recombination rates estimated by low-resolution genetic maps can only explain a small fraction of the variance between regions. We found that LD (in terms of r(2)) decreases as a function of distance even within the so-called 'haplotype blocks'. This has significant consequences when using LD mapping for the genetic dissection of complex traits, as higher density SNP maps will be required to scan the genome.

Alleles↗