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PubMed2001

Quantitative trait locus mapping: fishing strategy or replicable results?

Genomewide scan, as shown by recently published linkage studies on the behavior of mice or in psychiatry, provides evidence for replicated quantitative trait loci (QTL). Several studies of Alzheimer's disease have demonstrated the promise of moving from clinical diagnoses to biological signs for psychiatric investigations. Empirical studies also demonstrate that genetic background, differences in environment, epistatic effects, and definition of the phenotype (including psychiatric diagnosis) all actively contribute to limit the duplication of QTL.

Animals↗
PubMed2003

Recent advances in human quantitative-trait-locus mapping: comparison of methods for selected sibling pairs.

During the past few years, there has been a great deal of new work on methods for mapping quantitative-trait loci by use of sibling pairs and sibships. There are several new methods based on linear regression, as well as several more that are based on score statistics. In theory, most of the new methods should be relatively robust to violations of distributional assumptions and to selected sampling, but, in practice, there has been little evaluation of how the methods perform on selected samples. We survey most of the new regression-based statistics and score statistics and propose a few minor variations on the score statistics. We use simulation to evaluate the type I error and the power of all of the statistics, considering (a) population samples of sibling pairs and (b) sibling pairs ascertained on the basis of at least one sibling with a trait value in the top 10% of the distribution. Most of the statistics have correct type I error for selected samples. The statistics proposed by Xu et al. and by Sham and Purcell are generally the most powerful, along with one of our score statistic variants. Even among the methods that are most powerful for "nice" data, some are more robust than others to non-Gaussian trait models and/or misspecified trait parameters.

Chromosome Mapping↗
PubMed2004

Mouse inbred strain sequence information and yin-yang crosses for quantitative trait locus fine mapping.

The shared ancestry of mouse inbred strains, together with the availability of sequence and phenotype information, is a resource that can be used to map quantitative trait loci (QTL). The difficulty in using only sequence information lies in the fact that in most instances the allelic state of the QTL cannot be unambiguously determined in a given strain. To overcome this difficulty, the performance of multiple crosses between various inbred strains has been proposed. Here we suggest and evaluate a general approach, which consists of crossing the two strains used initially to map the QTL and any new strain. We have termed these crosses "yin-yang," because they are complementary in nature as shown by the fact that the QTL will necessarily segregate in only one of the crosses. We used the publicly available SNP database of chromosome 16 to evaluate the mapping resolution achievable through this approach. Although on average the improvement of mapping resolution using only four inbred strains was relatively small (i.e., reduction of the QTL-containing interval by half at most), we found a great degree of variability among different regions of chromosome 16 with regard to mapping resolution. This suggests that with a large number of strains in hand, selecting a small number of strains may provide a significant contribution to the fine mapping of QTL.

Alleles↗
PubMed1999

Genetic dissection of "OLETF," a rat model for non-insulin-dependent diabetes mellitus: quantitative trait locus analysis of (OLETF x BN) x OLETF.

To identify genetic determinants relevant to non-insulin-dependent diabetes mellitus (NIDDM), we performed a genome-wide analysis for quantitative trait loci (QTLs) using 359 backcross progeny of the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The OLETF strain is a well-studied animal model of obese NIDDM, with features of hyperinsulinemia, hyperglycemia, insulin resistance, and abundant abdominal fat. Our extensive genomic scanning with 218 markers revealed nine significant QTLs, including a strong determinant of obesity on chromosome 1 (Dmo1: LOD = 13.99, for body weight). Two highly significant QTLs for glucose homeostasis were found, one on chromosome 1 (Dmo4 LOD = 7.16, for postprandial glucose level) and the other on chromosome X (Dmo11/Odb1: LOD = 7.81, for postprandial glucose level). These data are comparable to results of our previous studies of the OLETF rat.

Adipose Tissue↗
PubMed2003

A quantitative trait locus on 7q31 for the changes in plasma insulin in response to exercise training: the HERITAGE Family Study.

Several genome-wide linkage scans have been carried out to identify quantitative trait loci for type 2 diabetes and related metabolic phenotypes. However, no previous linkage scans have focused on the response to exercise training of relevant metabolic traits. We performed a genome-wide linkage scan for baseline fasting glucose, insulin, and C-peptide and their responses to a 20-week exercise training program in nondiabetic white and black men and women from the HERITAGE Family Study. In SIBPAL linkage analyses, the maximum number of sibpairs available was 344 and 93 for baseline phenotypes and 300 and 72 for exercise training response phenotypes in whites and blacks, respectively. A total of 509 markers with an average spacing of 6.0 Mb were used. The strongest linkage was found for the changes in fasting insulin in response to exercise training with a marker in the leptin gene on 7q31 (empirical multipoint P = 0.0004) in whites. In blacks, the strongest linkage was observed for baseline fasting glucose on 12q13-q14 (empirical multipoint P = 0.0006). These regions harbor several potential candidate genes. The present findings may be important in identifying individuals at increased risk of developing type 2 diabetes and who are most likely to benefit from a physically active lifestyle.

Black People↗
PubMedDate not supplied

Prospects for quantitative trait locus methodology in gerontology.

The remarkable advances in mapping of genomes have made it feasible to search among the hitherto anonymous polygenes of complex systems for loci of intermediate effect size (quantitative trait loci-QTL). Pursuing the strategy of identifying these QTL in complex systems will open the possibility of exploring the genetic architecture and the anatomical, physiological, biochemical, and molecular mechanisms underlying the phenotypes under investigation. One study (Gelman et al., 1988) has pioneered the exploration of QTL in the study of aging. Their engaging results, dealing with age at death as the endpoint measure, portend the power of the search for quantitative trait loci in aging processes.

Aging↗
PubMed2003

Delimitation of the chromosomal region for a quantitative trait locus, qUVR- 10, conferring resistance to ultraviolet-B radiation in rice (Oryza sativa L.).

Wide variation in ultraviolet-B (UVB) resistance is observed among rice varieties. In a previous study, three quantitative trait loci (QTLs) controlling UVB resistance were detected by QTL analysis, using backcross inbred lines (BILs) derived from a cross between a japonica cultivar, 'Nipponbare', and an indica cultivar, 'Kasalath'. Among them, qUVR- 10, a QTL for UVB resistance on chromosome 10, showed the largest effect. Plants homozygous for the Nipponbare allele at qUVR- 10 were resistant to UVB, unlike those homozygous for the Kasalath allele. To determine more precisely the chromosomal location of qUVR- 10, we performed a linkage mapping of qUVR- 10 as a single Mendelian factor using advanced backcross progeny. Advanced progeny testing of F(4) families enabled us to determine the genotype classes of the qUVR- 10 locus with high reliability. As a result, qUVR- 10 was mapped between RFLP markers C60755S and C1757S, and co-segregated with C913A. In addition, a sequence showing high similarity to the Arabidopsis cyclobutane pyrimidine dimer (CPD) photolyase gene, which has been found to be involved in sensitivity to UV radiation in Arabidopsis and rice, was mapped in the candidate genomic region of qUVR- 10. This result suggests that the CPD photolyase gene is a positional candidate for qUVR- 10.

Chromosome Mapping↗
PubMed2006

Quantitative trait locus on Chromosome 19 for circulating levels of intercellular adhesion molecule-1 in Mexican Americans.

Circulating soluble intercellular adhesion molecule-1 (sICAM-1) is a biochemical marker of inflammation. We performed variance-components-based quantitative genetic analyses in SOLAR of sICAM-1 in 1170 individuals from Mexican American families in the San Antonio Family Heart Study. The trait is heritable (h(2)=0.50+/-0.06, P<10(-6)). Multipoint linkage analysis using a approximately 10-cM microsatellite map revealed a region on Chromosome 19p near marker D19S586 showing strong evidence of linkage for sICAM-1 (empirically adjusted univariate-equivalent LOD=4.95), coincident with the structural gene ICAM1. This region has been identified previously as a QTL for inflammatory, autoimmune, and metabolic syndrome traits. There is significant evidence (P=0.0023) of locus heterogeneity for sICAM-1 in this sample: a subset of pedigrees contributes most of the linkage signal for sICAM-1 on Chromosome 19, suggesting a logical focus for future genetic dissection of the trait.

Adult↗
PubMed2000

A recombination hotspot delimits a wild-species quantitative trait locus for tomato sugar content to 484 bp within an invertase gene.

In nature, genetic variation usually takes the form of a continuous phenotypic range rather than discrete classes. The genetic variation underlying quantitative traits results from the segregation of numerous interacting quantitative trait loci (QTLs), whose expression is modified by the environment. To uncover the molecular basis of this variation, we characterized a QTL (Brix9-2-5) derived from the green-fruited tomato species Lycopersicon pennellii. The wild-species allele increased glucose and fructose contents in cultivated tomato fruits in various genetic backgrounds and environments. Using nearly isogenic lines for the QTL, high-resolution mapping analysis delimited Brix9-2-5 to a single nucleotide polymorphism-defined recombination hotspot of 484 bp spanning an exon and intron of a fruit-specific apoplastic invertase. We suggest that the differences between the Brix9-2-5 alleles of the two species are associated with a polymorphic intronic element that modulates sink strength of tomato fruits. Our results demonstrate a link between naturally occurring DNA variation and a Mendelian determinant of a complex phenotype for a yield-associated trait.

Alleles↗
PubMed2001

Genetic isolation of a blood pressure quantitative trait locus on chromosome 2 in the spontaneously hypertensive rat.

OBJECTIVES: Total genome scans of genetically segregating populations derived from the spontaneously hypertensive rat (SHR) and other rat models of hypertension have suggested the presence of quantitative trait loci (QTL) regulating blood pressure and cardiac mass on multiple chromosomes, including chromosome 2. The objective of the current study was to directly test for the presence of a blood pressure QTL on rat chromosome 2. DESIGN: A new congenic strain was derived by replacing a segment of chromosome 2 in the SHR between D2Rat171 and D2Arb24 with the corresponding chromosome segment from the normotensive Brown Norway rat. Arterial pressures were directly monitored in conscious rats by radiotelemetry. RESULTS: We found that the SHR congenic strain (SHR-2) carrying a segment of chromosome 2 from the Brown Norway rat had significantly lower systolic and diastolic blood pressures than the SHR progenitor strain. The attenuation of hypertension in the SHR-2 congenic strain versus the SHR progenitor strain was accompanied by significant amelioration of cardiac hypertrophy. CONCLUSIONS: These findings demonstrate that gene(s) with major effects on blood pressure exist in the differential segment of chromosome 2 trapped within the new SHR.BN congenic strain.

Animals↗
PubMed2005

Quantitative trait locus analysis using recombinant inbred intercrosses: theoretical and empirical considerations.

We describe a new approach, called recombinant inbred intercross (RIX) mapping, that extends the power of recombinant inbred (RI) lines to provide sensitive detection of quantitative trait loci (QTL) responsible for complex genetic and nongenetic interactions. RIXs are generated by producing F1 hybrids between all or a subset of parental RI lines. By dramatically extending the number of unique, reproducible genomes, RIXs share some of the best properties of both the parental RI and F2 mapping panels. These attributes make the RIX method ideally suited for experiments requiring analysis of multiple parameters, under different environmental conditions and/or temporal sampling. However, since any pair of RIX genomes shares either one or no parental RIs, this cross introduces an unusual population structure requiring special computational approaches for analysis. Herein, we propose an efficient statistical procedure for QTL mapping with RIXs and describe a novel empirical permutation procedure to assess genome-wide significance. This procedure will also be applicable to diallel crosses. Extensive simulations using strain distribution patterns from CXB, AXB/BXA, and BXD mouse RI lines show the theoretical power of the RIX approach and the analysis of CXB RIXs demonstrates the limitations of this procedure when using small RI panels.

Animals↗
PubMed2003

Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees.

Using plasma amyloid beta protein (Abeta42) levels as an intermediate, quantitative phenotype for late onset Alzheimer's disease (LOAD), we previously obtained significant linkage at approximately 80 cM on chromosome 10. Linkage to the same region was obtained independently in a study of affected LOAD sib-pairs. Together, these two studies provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Abeta42. VR22 is a large (1.7 Mb) gene located at 80 cM that encodes alpha-T catenin, which is a binding partner of beta catenin. This makes VR22 an attractive candidate gene because beta catenin interacts with presenilin 1, which has many mutations that elevate Abeta42 and cause early onset familial AD. We identified two intronic VR22 SNPs (4360 and 4783) in strong linkage disequilibrium (LD) that showed highly significant association (P=0.0001 and 0.0006) with plasma Abeta42 in 10 extended LOAD families. This association clearly contributed to the linkage at approximately 80 cM because the lod scores decreased when linkage analysis was performed conditional upon the VR22 association. This association replicated in another independent set of 12 LOAD families (P=0.04 for 4783 and P=0.08 for 4360). Bounding of the association region using multiple SNPs showed VR22 to be the only confirmed gene within the region of association. These findings indicate that VR22 has variant(s) which influence Abeta42 and contribute to the previously reported linkage for plasma Abeta42 in LOAD families.

Adult↗
PubMed2002

Bias in estimates of quantitative-trait-locus effect in genome scans: demonstration of the phenomenon and a method-of-moments procedure for reducing bias.

An attractive feature of variance-components methods (including the Haseman-Elston tests) for the detection of quantitative-trait loci (QTL) is that these methods provide estimates of the QTL effect. However, estimates that are obtained by commonly used methods can be biased for several reasons. Perhaps the largest source of bias is the selection process. Generally, QTL effects are reported only at locations where statistically significant results are obtained. This conditional reporting can lead to a marked upward bias. In this article, we demonstrate this bias and show that its magnitude can be large. We then present a simple method-of-moments (MOM)-based procedure to obtain more-accurate estimates, and we demonstrate its validity via Monte Carlo simulation. Finally, limitations of the MOM approach are noted, and we discuss some alternative procedures that may also reduce bias.

Bias↗
PubMed2004

Major quantitative trait locus for eosinophil count is located on chromosome 2q.

BACKGROUND: Eosinophils are granulocytic white blood cells implicated in asthma and atopic disease. The degree of eosinophilia in the blood of patients with asthma correlates with the severity of asthmatic symptoms. Quantitative trait loci (QTL) linkage analysis of eosinophil count may be a more powerful strategy of mapping genes involved in asthma than linkage analysis using affected relative pairs. OBJECTIVE: To identify QTLs responsible for variation in eosinophil count in adolescent twins. METHODS: We measured eosinophil count longitudinally in 738 pairs of twins at 12, 14, and 16 years of age. We typed 757 highly polymorphic microsatellite markers at an average spacing of approximately 5 centimorgans across the genome. We then used multipoint variance components linkage analysis to test for linkage between marker loci and eosinophil concentrations at each age across the genome. RESULTS: We found highly significant linkage on chromosome 2q33 in 12-year-old twins (logarithm of the odds=4.6; P=.000002) and suggestive evidence of linkage in the same region in 14-year-olds (logarithm of the odds=1.0; P=.016). We also found suggestive evidence of linkage at other areas of the genome, including regions on chromosomes 2, 3, 4, 8, 9, 11, 12, 17, 20, and 22. CONCLUSION: A QTL for eosinophil count is present on chromosome 2q33. This QTL might represent a gene involved in asthma pathophysiology.

Adolescent↗
PubMed2005

An independent confirmation of a quantitative trait locus for milk yield and composition traits on bovine chromosome 26.

Several reports have demonstrated that bovine chromosome 26 (BTA26) harbours significant or suggestive quantitative trait loci (QTL) for milk production and composition traits in dairy cattle. Our previous study showed that a C/T substitution in the bovine TCF7L2 gene on BTA26 was significantly linked to QTL for protein yield (PY) in a Canadian dairy cattle population. Actually, this polymorphism was one of the markers derived from a genome-wide screening of QTL for milk PY using an amplified fragment length polymorphism technique combined with a DNA pooling strategy. In the present study, 990 Holstein bulls with complete genotype and phenotype data from 14 sire families were analysed to confirm, if the QTL effects exist in other populations. Statistical analysis revealed that this marker was significantly associated with PY, protein percentage, milk yield and fat yield (FY) (p < 0.001) in the US Holstein population. These results indicate that this QTL region has a pleiotrophic effecton different milk traits and is portable in different populations.

Analysis of Variance↗