Genomewide linkage scan for myopia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 22q12

Mild/moderate (common) myopia is a very common disorder, with both genetic and environmental influences. The environmental factors are related to near work and can be measured. There are no known genetic loci for common myopia. Our goal is to find evidence for a myopia susceptibility gene causing common myopia. Cycloplegic and manifest refraction were performed on 44 large American families of Ashkenazi Jewish descent, each with at least two affected siblings. Individuals with at least -1.00 diopter or lower in each meridian of both eyes were classified as myopic. Microsatellite genotyping with 387 markers was performed by the Center for Inherited Disease Research. Linkage analyses were conducted with parametric and nonparametric methods by use of 12 different penetrance models. The family-based association test was used for an association scan. A maximum multipoint parametric heterogeneity LOD (HLOD) score of 3.54 was observed at marker D22S685, and nonparametric linkage analyses gave consistent results, with a P value of.0002 at this marker. The parametric multipoint HLOD scores exceeded 3.0 for a 4-cM interval, and significant evidence of genetic heterogeneity was observed. This genomewide scan is the first step toward identifying a gene on chromosome 22 with an influence on common myopia. At present, we are following up our linkage results on chromosome 22 with a dense map of >1,500 single-nucleotide-polymorphism markers for fine mapping and association analyses. Identification of a susceptibility locus in this region may eventually lead to a better understanding of gene-environment interactions in the causation of this complex trait.     

Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22

Previous linkage studies in schizophrenia have been discouraging due to inconsistent findings and weak signals. Genetic heterogeneity has been cited as one of the primary culprits for such inconsistencies. We have performed a 10-cM autosomal genomewide linkage scan for schizophrenia susceptibility regions, using 29 multiplex families of Ashkenazi Jewish descent. Although there is no evidence that the rate of schizophrenia among the Ashkenazim differs from that in other populations, we have focused on this population in hopes of reducing genetic heterogeneity among families and increasing the detectable effects of any particular locus. We pursued both allele-sharing and parametric linkage analyses as implemented in Genehunter, version 2.0. Our strongest signal was achieved at chromosome 10q22.3 (D10S1686), with a nonparametric linkage score (NPL) of 3.35 (genomewide empirical P=.035) and a dominant heterogeneity LOD score (HLOD) of 3.14. Six other regions gave NPL scores >2.00 (on chromosomes 1p32.2, 4q34.3, 6p21.31, 7p15.2, 15q11.2, and 21q21.2). Upon follow-up with an additional 23 markers in the chromosome 10q region, our peak NPL score increased to 4.27 (D10S1774; empirical P=.00002), with a 95% confidence interval of 12.2 Mb for the location of the trait locus (D10S1677 to D10S1753). We find these results encouraging for the study of schizophrenia among Ashkenazi families and suggest further linkage and association studies in this chromosome 10q region.     

Confirmation and fine‐mapping of clinical mastitis and somatic cell score QTL in Nordic Holstein cattle

A genome‐wide association study of 2098 progeny‐tested Nordic Holstein bulls genotyped for 36 387 SNPs on 29 autosomes was conducted to confirm and fine‐map quantitative trait loci (QTL) for mastitis traits identified earlier using linkage analysis with sparse microsatellite markers in the same population. We used linear mixed model analysis where a polygenic genetic effect was fitted as a random effect and single SNPs were successively included as fixed effects in the model. We detected 143 SNP‐by‐trait significant associations (P < 0.0001) on 20 chromosomes affecting mastitis‐related traits. Among them, 21 SNP‐by‐trait combinations exceeded the genome‐wide significant threshold. For 12 chromosomes, both the present association study and the previous linkage study detected QTL, and of these, six were in the same chromosomal locations. Strong associations of SNPs with mastitis traits were observed on bovine autosomes 6, 13, 14 and 20. Possible candidate genes for these QTL were identified. Identification of SNPs in linkage disequilibrium with QTL will enable marker‐based selection for mastitis resistance. The candidate genes identified should be further studied to detect candidate polymorphisms underlying these QTL.     

Construction of a linkage map based on a <Emphasis Type="Italic">Lathyrus sativus</Emphasis> backcross population and preliminary investigation of QTLs associated with resistance to ascochyta blight

A linkage map of the Lathyrus sativus genome was constructed using 92 backcross individuals derived from a cross between an accession resistant (ATC 80878) to ascochyta blight caused by Mycosphaerella pinodes and a susceptible accession (ATC 80407). A total of 64 markers were mapped on the backcross population, including 47 RAPD, seven sequence-tagged microsatellite site and 13 STS/CAPS markers. The map comprised nine linkage groups, covered a map distance of 803.1 cM, and the average spacing between markers was 15.8 cM. Quantitative trait loci (QTL) associated with ascochyta blight resistance were detected using single-point analysis and simple and composite interval mapping. The backcross population was evaluated for stem resistance in temperature-controlled growth room trials. One significant QTL, QTL1, was located on linkage group 1 and explained 12% of the phenotypic variation in the backcross population. A second suggestive QTL, QTL2, was detected on linkage group 2 and accounted for 9% of the trait variation. The L. sativus R-QTL regions detected may be targeted for future intergenus transfer of the trait into accessions of the closely related species Pisum sativum.     

Genomewide markers as cofactors for precision mapping of quantitative trait loci

In composite interval mapping of quantitative trait loci (QTL), subsets of background markers are used to account for the effects of QTL outside the marker interval being tested. Here, I propose a QTL mapping approach (called G model) that utilizes genomewide markers as cofactors. The G model involves backward elimination on a given chromosome after correcting for genomewide marker effects, calculated under a random effects model, at all the other chromosomes. I simulated a trait controlled by 15 or 30 QTL, mapping populations of N = 96, 192, and 384 recombinant inbreds, and N _M = 192 and 384 evenly spaced markers. In the C model, which utilized subsets of background markers, the number of QTL detected and the number of false positives depended on the number of cofactors used, with five cofactors being too few with N = 384 and 20–40 cofactors being too many with N = 96. A window size of 0 cM for excluding cofactors maintained the number of true QTL detected while decreasing the number of false positives. The number of true QTL detected was generally higher with the G model than with the C model, and the G model led to good control of the type I error rate in simulations where the null hypothesis of no marker–QTL linkage was true. Overall, the results indicated that the G model is useful in QTL mapping because it is less subjective and has equal, if not better, performance when compared with the traditional approach of using subsets of markers to account for background QTL.     

Major quantitative trait loci affect resistance to infectious pancreatic necrosis in Atlantic salmon (Salmo salar)

Infectious pancreatic necrosis (IPN) is a viral disease currently presenting a major problem in the production of Atlantic salmon (Salmon salar). IPN can cause significant mortality to salmon fry within freshwater hatcheries and to smolts following transfer to seawater, although challenged populations show clear genetic variation in resistance. To determine whether this genetic variation includes loci of major effect, a genomewide quantitative trait loci (QTL) scan was performed within 10 full-sib families that had received a natural seawater IPN challenge. To utilize the large difference between Atlantic salmon male and female recombination rates, a two-stage mapping strategy was employed. Initially, a sire-based QTL analysis was used to detect linkage groups with significant effects on IPN resistance, using two to three microsatellite markers per linkage group. A dam-based analysis with additional markers was then used to confirm and position any detected QTL. Two genomewide significant QTL and one suggestive QTL were detected in the genome scan. The most significant QTL was mapped to linkage group 21 and was significant at the genomewide level in both the sire and the dam-based analyses. The identified QTL can be applied in marker-assisted selection programs to improve the resistance of salmon to IPN and reduce disease-related mortality.     

A susceptibility locus for myopia in the normal population is linked to the PAX6 gene region on chromosome 11: a genomewide scan of dizygotic twins

Myopia is a common, complex trait with considerable economic and social impact and, in highly affected individuals, ocular morbidity. We performed a classic twin study of 506 unselected twin pairs and inferred the heritability of refractive error to be 0.89 (95% confidence interval 0.86-0.91). A genomewide scan of 221 dizygotic twin pairs, analyzed by use of optimal Haseman-Elston regression methods implemented by use of generalized linear modeling, showed significant linkage (LOD >3.2) to refractive error at four loci, with a maximum LOD score of 6.1 at 40 cM on chromome 11p13. Evidence of linkage at this locus, as well as at the other linkage peaks at chromosomes 3q26 (LOD 3.7), 8p23 (LOD 4.1), and 4q12 (LOD 3.3), remained the same or became stronger after model fit was checked and outliers were downweighted. Examination of potential candidate genes showed the PAX6 gene directly below the highest peak at the 11p13 locus. PAX6 is fundamental to identity and growth of the eye, but reported mutations usually result in catastrophic congenital phenotypes such as aniridia. Haplotype tagging of 17 single-nucleotide polymorphisms (SNPs), which covered the PAX6 gene and had common minor allele frequencies, identified 5 SNPs that explained 0.999 of the haplotype diversity. Linkage and association analysis of the tagging SNPs showed strong evidence of linkage for all markers with a minimum chi 21 of 7.5 (P=.006) but no association. This suggests that PAX6 may play a role in myopia development, possibly because of genetic variation in an upstream promoter or regulator, although no definite association between PAX6 common variants and myopia was demonstrated in this study.     

Evidence that a locus for familial high myopia maps to chromosome 18p.

Myopia, or nearsightedness, is the most common human eye disorder. A genomewide screen was conducted to map the gene(s) associated with high, early-onset, autosomal dominant myopia. Eight families that each included two or more individuals with >=-6.00 diopters (D) myopia, in two or more successive generations, were identified. Myopic individuals had no clinical evidence of connective-tissue abnormalities, and the average age at diagnosis of myopia was 6.8 years. The average spherical component refractive error for the affected individuals was -9.48 D. The families contained 82 individuals; of these, DNA was available for 71 (37 affected). Markers flanking or intragenic to the genes for Stickler syndrome types 1 and 2 (chromosomes 12q13.1-q13.3 and 6p21.3, respectively), Marfan syndrome (chromosome 15q21.1), and juvenile glaucoma (chromosome 1q21-q31) were also analyzed. No evidence of linkage was found for markers for the Stickler syndrome types 1 and 2, the Marfan syndrome, or the juvenile glaucoma loci. After a genomewide search, evidence of significant linkage was found on chromosome 18p. The maximum LOD score was 9.59, with marker D18S481, at a recombination fraction of .0010. Haplotype analysis further refined this myopia locus to a 7.6-cM interval between markers D18S59 and D18S1138 on 18p11.31.     

Quantitative trait loci in Chromosomes 3, 8, and 9 regulate antibody production against <Emphasis Type="Italic">Salmonella</Emphasis> flagellar antigensin the mouse

Two mouse lines were produced by bidirectional selection according to the high (HIII) or low (LIII) antibody responsiveness against Salmonella flagellar antigens (Selection III). In the present work we conducted a genomewide scan to map the quantitative trait loci (QTL) involved in the antibody response regulation in these selected mice. HIII and LIII genomes were screened with microsatellite markers and those found polymorphic between the lines (146) were used for linkage analysis in F2 (HIII × LIII) intercross. Simple interval mapping analysis was performed using Mapmanager QTX software. Three highly significant QTL linked to antibody production against Salmonella flagellar antigens have been demonstrated in Chromosomes 3, 8, and 9. HIII and LIII lines differ in the resistance to several diseases, therefore, the relevance of these QTL with the genetic factors involved in infections, autoimmunity, and neoplastic disease progression is discussed.     

近视眼LASIK术后眼高阶像差变化

探讨近视眼LASIK术后眼波阵面像差高阶像差各项的变化。方法:采用NIDEK OPD-Scan ARK-1000型波前像差扫描系统对LASIK治疗近视的62只眼在术前术后眼的波前像差进行了评估。在术前、术后10天、术后一个月分别测量眼的波阵面像差。比较6mm瞳孔下高阶像差各项的变化。结果:在全部接受检查的病例中,总的高阶像差(RMSh)均有所增加。从Zernik各项绝对值来看,球差C12变化最大。术后10天比术前增加6．7742倍(P=0．0001)。其次是彗差C7 C8(X轴、Y轴上的彗差),分别增加了4．883倍(P=0．0001)、3．7523倍(P=0．0001)。结论:LASIK术后眼的总的高阶像差均方根值(RMSh)明显增加,尤其是球差和彗差;但在恢复过程中高阶像差有下降的趋势。用像差仪来指导和评估LASIK等屈光手术可以更全面、更准确。     

Quantitative trait locus on chromosome 12q14.1 influences variation in plasma plasminogen levels in the San Antonio Family Heart Study

Plasminogen is a hemostasis-related phenotype and is commonly implicated in thrombotic and bleeding disorders. In the San Antonio Family Heart Study (SAFHS), we performed to our knowledge the first genomewide linkage scan for quantitative trait loci (QTLs) that influence the level of plasminogen. The subset of the SAFHS population used for this study consists of 629 individuals distributed across 26 extended Mexican American families. Pedigree-based variance component linkage analyses were performed using SOLAR. The mean plasminogen level was 114.94% +/- 17.8 (range, 42-195). The heritability (h2) of plasminogen was 0.43 +/- 0.08 (p < 6.3 x 10(-13)). One region on chromosome 12 (12q14.1) showed suggestive evidence of linkage (LOD = 2.73, nominal p < 0.0002, genomewide p = 0.0786) near marker D12S1609. Because plasminogen has important effects in many human health problems, such as cancer and atherosclerosis, the role of this putative QTL in the regulation of plasminogen variability needs to be studied further.     

Identification of QTL for reaction to three races of <Emphasis Type="Italic">Colletotrichum trifolii</Emphasis> and further analysis of inheritance of resistance in autotetraploid lucerne

Anthracnose, caused by Colletotrichum trifolii, is one of the most serious diseases of lucerne worldwide. The disease is managed through deployment of resistant cultivars, but new pathotypes present a challenge to the successful implementation of this strategy. This paper reports the genetic map locations of quantitative trait loci (QTL) for reaction to races 1, 2 and 4 of C. trifolii in a single autotetraploid lucerne clone, designated W126 from the Australian cv. Trifecta. Resistance was mapped in a backcross population of 145 individuals, and reaction was assessed both by spray and injection inoculation of stems. Resistance to injection inoculation with races 1 and 4 was incompletely dominant and closely linked (phenotypic markers 2.2 cM apart); these resistances mapped to a linkage group homologous to Medicago truncatula linkage group 8. When the spray inoculation data were subjected to QTL analysis, the strongest QTL for resistance was located on linkage group 8; six QTL were identified for race 1 and four for race 4. Resistance to race 2 was incompletely recessive; four QTL were identified and these include one QTL on linkage group 4 that was also identified for race 1. Modelling of the interactions between individual QTL and marker effects allowed a total of 52–63% of the phenotypic variation to be described for each of the different races. These markers will have value in breeding lucerne, carrying multiple sources of resistance to the three known races of C. trifolii.     

Quantitative trait loci associated with red foliage in <Emphasis Type="Italic">Cornus florida</Emphasis> L.

The objective of our investigation was to acquire information on the association between molecular markers and foliage color in flowering dogwood in order to improve our understanding of the inheritance of this trait and to make possible early selection of red foliage genotypes in breeding programs. A segregating pseudo-F₂ population of 94 individuals of flowering dogwood (Cornus florida L.), together with 255 simple sequence repeat markers, was used to identify putative quantitative trait loci (QTL) for foliage color. Foliage color segregated into green- and red-leaved phenotypes and was visually rated for color on five spring dates over 3 years (2007–2009). Repeated measures single-marker categorical analysis of variance (ANOVA) identified four putative QTL (CF309C, CF792A, CF367B, and CF367C) on three linkage groups. Single-marker categorical ANOVA was then used to determine stability of QTL across dates. We identified different QTL, found a low percentage of phenotypic variance explained by the QTL, and detected QTL instability over time, providing evidence of the complex genetics for red pigment expression in flowering dogwood.     

Association between Ocular Sensory Dominance and Refractive Error Asymmetry

Purpose

To investigate the association between ocular sensory dominance and interocular refractive error difference (IRED).

Methods

A total of 219 subjects were recruited. The refractive errors were determined by objective refraction with a fixation target located 6 meters away. 176 subjects were myopic, with 83 being anisometropic (IRED ≥ 0.75 D). 43 subjects were hyperopic, with 22 being anisometropic. Sensory dominance was measured with a continuous flashing technique with the tested eye viewing a Gabor increasing in contrast and the fellow eye viewing a Mondrian noise decreasing in contrast. The log ratio of Mondrian to Gabor’s contrasts was recorded when a subject just detected the tilting direction of the Gabor during each trial. T-test was used to compare the 50 values collected from each eye, and the t-value was used as a subject’s ocular dominance index (ODI) to quantify the degree of ocular dominance. A subject with ODI ≥ 2 (p < 0.05) had clear dominance and the eye with larger mean ratio was the dominant one. Otherwise, a subject had an unclear dominance.

Results

The anisometropic subjects had stronger ocular dominance in comparison to non-anisometropic subjects (rank-sum test, p < 0.01 for both myopic and hyperopic subjects). In anisometropic subjects with clear dominance, the amplitude of the anisometropia was correlated with ODI values (R = 0.42, p < 0.01 in myopic anisometropic subjects; R = 0.62, p < 0.01 in hyperopic anisometropic subjects). Moreover, the dominant eyes were more myopic in myopic anisometropic subjects (sign-test, p < 0.05) and less hyperopic in hyperopic anisometropic subjects (sign-test, p < 0.05).

Conclusion

The degree of ocular sensory dominance is associated with interocular refractive error difference.     

Mapping of the mucolipidosis type IV gene to chromosome 19p and definition of founder haplotypes.

Mucolipidosis type IV (MLIV) is a lysosomal storage disorder characterized by severe neurologic and ophthalmologic abnormalities. It is a rare autosomal recessive disease, and the majority of patients diagnosed, to date, are of Ashkenazi Jewish descent. We have mapped the MLIV gene to chromosome 19p13.2-13.3 by linkage analysis with 15 markers in 13 families. A maximum LOD score of 5.51 with no recombinants was observed with marker D19S873. Several markers in the linked interval also displayed significant linkage disequilibrium with the disorder. We constructed haplotypes in 26 Ashkenazi Jewish families and demonstrate the existence of two founder chromosomes in this population. The localization of MLIV to chromosome 19 will permit genetic prenatal diagnosis in affected families and will aid in the isolation of the disease gene.     

Improving the power of sib pair quantitative trait loci detection by phenotype winsorization

OBJECTIVES: In sib pair studies, quantitative trait loci (QTL) identification may be adversely affected by non-normality in the phenotypic distribution, particularly when subjects falling in the tails of the distribution bias the trait mean or variance. We evaluated the robustness and power of reducing the influence of subjects with extreme phenotypic values by Winsorizing non-normal distributions in three versions of Haseman-Elston regression-based methods of QTL linkage analysis. METHODS: Data were simulated for normal and non-normal distributions. Phenotypic values that correspond to cutoff points at the omega and 1 - omega percentiles of the distribution were identified, and phenotypic values falling outside the boundaries of the omega and 1 - omega cutoff points were replaced by the omega and 1 - omega values, respectively. One million replications were performed for the three tests of linkage for Winsorized and non-Winsorized data. RESULTS: Winsorization reduced conservatism in the tails of the empirical type I error rate for the vast majority of the tests of linkage, increased the power of QTL detection in non-normal data and created a slight negative bias in symmetrical phenotypic distributions. CONCLUSIONS: Winsorizing can improve the power of QTL detection with certain non-normal distributions but can also introduce bias into the estimate of the QTL effect.     

Genomewide Linkage Analysis of Stature in Multiple Populations Reveals Several Regions with Evidence of Linkage to Adult Height

Genomewide linkage analysis has been extremely successful at identification of the genetic variation underlying single-gene disorders. However, linkage analysis has been less successful for common human diseases and other complex traits in which multiple genetic and environmental factors interact to influence disease risk. We hypothesized that a highly heritable complex trait, in which the contribution of environmental factors was relatively limited, might be more amenable to linkage analysis. We therefore chose to study stature (adult height), for which heritability is approximately 75%-90% (Phillips and Matheny 1990; Carmichael and McGue 1995; Preece 1996; Silventoinen et al. 2000). We reanalyzed genomewide scans from four populations for which genotype and height data were available, using a variance-components method implemented in GENEHUNTER 2.0 (Pratt et al. 2000). The populations consisted of 408 individuals in 58 families from the Botnia region of Finland, 753 individuals in 183 families from other parts of Finland, 746 individuals in 179 families from Southern Sweden, and 420 individuals in 63 families from the Saguenay-Lac-St.-Jean region of Quebec. Four regions showed evidence of linkage to stature: 6q24-25, multipoint LOD score 3.85 at marker D6S1007 in Botnia (genomewide P<.06), 7q31.3-36 (LOD 3.40 at marker D7S2195 in Sweden, P<.02), 12p11.2-q14 (LOD 3.35 at markers D12S10990-D12S398 in Finland, P<.05) and 13q32-33 (LOD 3.56 at markers D13S779-D13S797 in Finland, P<.05). In a companion article (Perola et al. 2001 [in this issue]), strong supporting evidence is obtained for linkage to the region on chromosome 7. These studies suggest that highly heritable complex traits such as stature may be genetically tractable and provide insight into the genetic architecture of complex traits.     

Identification of QTL for resistance and susceptibility to <Emphasis Type="Italic">Stagonospora meliloti</Emphasis> in autotetraploid lucerne

In eastern Australia and California, USA, one of the major lethal fungal diseases of lucerne (Medicago sativa) is Stagonospora root and crown rot, caused by Stagonospora meliloti. Quantitative trait loci (QTL) involved in resistance and susceptibility to S. meliloti were identified in an autotetraploid lucerne backcross population of 145 individuals. Using regression analysis and interval mapping, we detected one region each on linkage groups 2, 6 and 7 that were consistently associated with disease reaction to S. meliloti in two separate experiments. The largest QTL on linkage group 7, which is associated with resistance to S. meliloti, contributed up to 17% of the phenotypic variation. The QTL located on linkage group 2, which is potentially a resistance allele in repulsion to the markers for susceptibility to S. meliloti, contributed up to 8% of the phenotypic variation. The QTL located on linkage group 6, which is associated with susceptibility to S. meliloti, contributed up to 16% of the phenotypic variation. A further two unlinked markers contributed 5 and 8% of the phenotypic variation, and were detected in only one experiment. A total of 517 simple sequence repeat (SSR) markers from Medicago truncatula were screened on the parents of the mapping population. Only 27 (6%) SSR markers were polymorphic and could be incorporated into the autotetraploid map of M. sativa. This allowed alignment of our M. sativa linkage map with published M. truncatula maps. The markers linked to the QTL we have reported will be useful for marker assisted selection for partial resistance to S. meliloti in lucerne.     

Detection of linkage between quantitative trait loci and restriction fragment length polymorphisms using inbred lines

Summary In segregating populations, large numbers of individuals are needed to detect linkage between markers, such as restriction fragment length polymorphisms (RFLPs), and quantitative trait loci (QTL), limiting the potential use of such markers for detecting linkage. Fewer individuals from inbred lines are needed to detect linkage. Simulation data were used to test the utility of two methods to detect linkage: maximum likelihood and comparison of marker genotype means. When there is tight linkage, the two methods have similar power, but when there is loose linkage, maximum likelihood is much more powerful. Once inbred lines have been established, they can be screened rapidly to detect QTL for several traits simultaneously. If there is sufficient coverage of the genome with RFLPs, several QTL for each trait may be detected.     

Construction of a framework map for Pinus koraiensis Sieb. et Zucc. using SRAP, SSR and ISSR markers

Genetic linkage maps are essential for molecular breeding program. The first genetic linkage map of Pinus koraiensis, using an F1 progeny of 94 individuals, was constructed in the present paper. One hundred and twenty-two molecular markers were mapped onto 11 linkage groups, 1 triple and 8 pairs at the linkage criteria LOD 4.0. Among these markers, there were 96 sequence-related amplified polymorphism (SRAP) markers, 25 simple sequence repeat (SSR) markers, and 1 inter-simple sequence repeat (ISSR) marker. The consensus map gained covers 857.464 cM Kosambi (K) with an average marker spacing of 7.03 cM K. The presented map provides a basis and crucial information for future genomic studies of P. koraiensis, in particular for quantitative trait loci (QTL) mapping of economically important breeding target traits.