Highest Logarithm Of Odds Score Research Articles

Role of an Atypical Cadherin Gene, Cdh23 in Prepulse Inhibition, and Implication of CDH23 in Schizophrenia.

We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.

Positional cloning and comprehensive mutation analysis identified a novel KDM2B mutation in a Japanese family with minor malformations, intellectual disability, and schizophrenia.

The importance of epigenetic control in the development of the central nervous system has recently been attracting attention. Methylation patterns of lysine 4 and lysine 36 in histone H3 (H3K4 and H3K36) in the central nervous system are highly conserved among species. Numerous complications of body malformations and neuropsychiatric disorders are due to abnormal histone H3 methylation modifiers. In this study, we analyzed a Japanese family with a dominant inheritance of symptoms including Marfan syndrome-like minor physical anomalies (MPAs), intellectual disability, and schizophrenia (SCZ). We performed positional cloning for this family using a single nucleotide polymorphism (SNP) array and whole-exome sequencing, which revealed a missense coding strand mutation (rs1555289644, NM_032590.4: c.2173G>A, p.A725T) in exon 15 on the plant homeodomain of the KDM2B gene as a possible cause of the disease in the family. The exome sequencing revealed that within the coding region, only a point mutation in KDM2B was present in the region with the highest logarithm of odds score of 2.41 resulting from whole genome linkage analysis. Haplotype analysis revealed co-segregation with four affected family members (IV-9, III-4, IV-5, and IV-8). Lymphoblastoid cell lines from the proband with this mutation showed approximately halved KDM2B expression in comparison with healthy controls. KDM2B acts as an H3K4 and H3K36 histone demethylase. Our findings suggest that haploinsufficiency of KDM2B in the process of development, like other H3K4 and H3K36 methylation modifiers, may have caused MPAs, intellectual disability, and SCZ in this Japanese family.

In the presence of population structure: From genomics to candidate genes underlying local adaptation.

Understanding the genomic signatures, genes, and traits underlying local adaptation of organisms to heterogeneous environments is of central importance to the field evolutionary biology. To identify loci underlying local adaptation, models that combine allelic and environmental variation while controlling for the effects of population structure have emerged as the method of choice. Despite being evaluated in simulation studies, there has not been a thorough investigation of empirical evidence supporting local adaptation across these alleles. To evaluate these methods, we use 875 Arabidopsis thaliana Eurasian accessions and two mixed models (GEMMA and LFMM) to identify candidate SNPs underlying local adaptation to climate. Subsequently, to assess evidence of local adaptation and function among significant SNPs, we examine allele frequency differentiation and recent selection across Eurasian populations, in addition to their distribution along quantitative trait loci (QTL) explaining fitness variation between Italy and Sweden populations and cis‐regulatory/nonsynonymous sites showing significant selective constraint. Our results indicate that significant LFMM/GEMMA SNPs show low allele frequency differentiation and linkage disequilibrium across locally adapted Italy and Sweden populations, in addition to a poor association with fitness QTL peaks (highest logarithm of odds score). Furthermore, when examining derived allele frequencies across the Eurasian range, we find that these SNPs are enriched in low‐frequency variants that show very large climatic differentiation but low levels of linkage disequilibrium. These results suggest that their enrichment along putative functional sites most likely represents deleterious variation that is independent of local adaptation. Among all the genomic signatures examined, only SNPs showing high absolute allele frequency differentiation (AFD) and linkage disequilibrium (LD) between Italy and Sweden populations showed a strong association with fitness QTL peaks and were enriched along selectively constrained cis‐regulatory/nonsynonymous sites. Using these SNPs, we find strong evidence linking flowering time, freezing tolerance, and the abscisic‐acid pathway to local adaptation.

English

Anthracnose (Colletotrichum lindemuthianum), Angular leaf spot (Pseudocercospora griseola) and Pythium root rot are important pathogens affecting common bean production in the tropics. A promising strategy to manage these diseases consists of combining several resistance (R) genes into one cultivar. The aim of the study was to determine genetic linkage between gene pairs, Co-42/Phg-2, on bean-chromosome Pv08 and Co-5/“P.ult” on-chromosome Pv07, to increase the efficiency of dual selection of resistance genes for major bean diseases, with molecular markers. The level of recombination was determined by tracking molecular markers for both BC3F6 and F2 generations. Recombination fraction r, among gene pairs, the likelihood of linkage, L(r), and logarithm of odds (LOD) scores were computed using the statistical relationship of likelihood which assumes a binomial distribution. The SCAR marker pair SAB3/PYAA19 for the gene pair Co-5/“P.ult” exhibited moderate linkage (r = 32 cM with a high LOD score of 9.2) for BC3F6 population, but relatively stronger linkage for the F2 population (r = 21 cM with a high LOD score of 18.7). However, the linkage among SCAR marker pair SH18/SN02, for the gene pair Co-42/Phg-2 was incomplete for BC3F6 population (r = 47 cM with a low LOD score of 0.16) as well as F2 population (r = 44 cM with a low LOD score of 0.7). Generally, the weak or incomplete genetic linkage between marker pairs studied showed that all the four genes mentioned earlier have to be tagged with a corresponding linked marker during selection. The approaches used in this study will contribute to two loci linkage mapping techniques in segregating plant populations.

The Lr46 Gene Conditions Partial Adult‐ Plant Resistance to Stripe Rust, Stem Rust, and Powdery Mildew in Thatcher Wheat

ABSTRACTDisease resistance is a critical goal for many wheat (Triticum aestivum L.) improvement programs. Wheat cultivars are affected by multiple diseases including the rusts and powdery mildew. The F6 recombinant inbred lines (RILs) derived from ‘Thatcher’∗3/‘CI13227’ that had been previously characterized as having adult‐plant leaf rust resistance gene Lr46 were further tested for resistance to stripe rust, stem rust, and powdery mildew. In field plot tests, the RILs segregated for resistance to stripe rust, stem rust, and powdery mildew, with the highest logarithm of odds (LOD) peak at the sequence tagged site marker csLV46, which is closely linked to Lr46 on chromosome 1BL. Marker csLV46 had the highest LOD scores and R2 values for powdery mildew resistance, followed by stripe rust and leaf rust resistance. Tests for stem rust resistance had the lowest LOD scores. An additional quantitative trait locus (QTL) on chromosome 7AL for leaf rust resistance derived from CI13227 was detected in two of the three leaf rust tests. A QTL for stem rust resistance on chromosome 7AL derived from Thatcher was detected in two of the three stem rust tests.

Identification of a novel major locus for gray leaf spot resistance in Italian ryegrass (Lolium multiflorum Lam.).

BackgroundGray leaf spot (GLS), caused by Magnaporthe oryzae (anamorph Pyricularia oryzae), in ryegrasses is a very serious problem. Heavily infected small seedlings die within a matter of days, and stands of the grasses are seriously damaged by the disease. Thus, the development of GLS-resistant cultivars has become a concern in ryegrass breeding.ResultsPhenotypic segregations in a single cross-derived F1 population of Italian ryegrass (Lolium multiflorum Lam.) indicated that the GLS resistance in the population was possibly controlled by one or two dominant genes with 66.5–77.9% of broad-sense heritability. In bulked segregant analyses, two simple sequence repeat (SSR) markers, which have so far been reported to locate on linkage group (LG) 3 of Italian ryegrass, showed specific signals in the resistant parent and resistant bulk, indicating that the resistance gene locus was possibly in the LG 3. We thus constructed a genetic linkage map of the LG 3 covering 133.6 centimorgan with other SSR markers of the LG 3 of Italian ryegrass and grass anchor probes that have previously been assigned to LG 3 of ryegrasses, and with rice expressed sequence tag (EST)-derived markers selected from a rice EST map of chromosome (Chr) 1 since LG 3 of ryegrasses are syntenic to rice Chr 1. Quantitative trait locus (QTL) analysis with the genetic linkage map and phenotypic data of the F1 population detected a major locus for GLS resistance. Proportions of phenotypic variance explained by the QTL at the highest logarithm of odds scores were 61.0–69.5%.ConclusionsA resistance locus was confirmed as novel for GLS resistance, because its genetic position was different from other known loci for GLS resistance. Broad-sense heritability and the proportion of phenotypic variance explained by the QTL were similar, suggesting that most of the genetic factors for the resistance phenotype against GLS in the F1 population can be explained by a function of the single resistance locus. We designated the putative gene for the novel resistance locus as LmPi2. LmPi2 will be useful for future development of GLS-resistant cultivars in combination with other resistance genes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12870-014-0303-6) contains supplementary material, which is available to authorized users.

Single nucleotide polymorphism rs3732860 in the 3′‐untranslated region of CYP8B1 gene is associated with gallstone disease in Han Chinese

Gallstone disease (GD) is a common disease of multigenetic origin; however, the major susceptibility loci for GD in human populations remain unidentified. This study aimed to identify the genetic factors contributing to gallstone development in Chinese. A genome-wide scan was conducted in 12 Han Chinese GD families to identify linkage loci. The linkage region showing the highest logarithm of odds score encompasses the sterol 12α-hydroxylase gene (CYP8B1). Replication analysis with an independent sample of 192 GD patients and 192 unrelated, matched controls was carried out to verify the associations between CYP8B1 polymorphisms and GD. Three loci (D3S1266, D4S406, and D9S1682) showed suggestive or nominal evidence of linkage in all 12 GD families. The logarithm of odds score of D3S1266 reached 2.71 in the families with late-onset patients. The single nucleotide polymorphism rs3732860 in the 3'-untranslated region of CYP8B1 showed significant association to GD (P = 0.022), and carriers of the A allele had lower risk of GD (odds ratio = 1.46, 95% confidence interval: 1.055-2.034) compared with carriers of the G allele. The single nucleotide polymorphism rs3732860 in the 3'-untranslated region of the CYP8B1 gene is associated with risk of GD in Chinese Han and appears to be responsible for the observed linkage with D3S1266.

Partial SPAST and DPY30 deletions in a Japanese spastic paraplegia type 4 family

Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant hereditary SPG caused by mutations in the SPAST gene. We studied the four-generation pedigree of a Japanese family with autosomal dominant hereditary SPG both clinically and genetically. Twelve available family members (ten affected; two unaffected) and two spouses were enrolled in the study. The clinical features were hyperreflexia in all four limbs, spasticity of the lower extremities, impaired vibration sense, mild cognitive impairment confirmed by the Wechsler Adult Intelligence Scale-Third Edition, and peripheral neuropathy confirmed by neurophysiological examinations. All four female patients experienced miscarriages. The cerebrospinal fluid tau levels were mildly increased in two of three patients examined. Linkage analyses revealed the highest logarithm of odds score of 2.64 at 2p23-p21 where the SPAST gene is located. Mutation scanning of the entire exonic regions of the SPAST gene by direct sequencing revealed no mutations. Exonic copy number analysis by real-time quantitative polymerase chain reaction revealed heterozygous deletion of exons 1 to 4 of the SPAST gene. Breakpoint analysis showed that the centromeric breakpoint was located within intron 4 of SPAST while the telomeric breakpoint was located within intron 3 of the neighboring DPY30 gene, causing a deletion of approximately 70 kb ranging from exons 1 to 3 of DPY30 to exons 1 to 4 of SPAST. To our knowledge, this is the first report of SPG4 associated with partial deletions of both the SPAST and DPY30 genes. The partial heterozygous deletion of DPY30 could modify the phenotypic expression of SPG4 patients with this pedigree.

Genetic effect on blood pressure is modulated by age: the Hypertension Genetic Epidemiology Network Study.

Genome-wide linkage analysis was performed for systolic and diastolic blood pressures in the Hypertension Genetic Epidemiology Network. We investigated the role of gene-age interactions using a recently developed variance components method that incorporates age variation in genetic effects. Substantially improved linkage evidence, in terms of both the number of linkage peaks and their significance levels, was observed. Twenty-six linkage peaks were identified with maximum logarithm of odds scores ranging between 3.0 and 4.6, 15 of which were cross-validated by the literature. The chromosomal region 1p36 that showed the highest logarithm of odds score in our study was found to be supported by evidence from 3 studies. The new method also led to vastly improved validation across ethnic groups. Ten of the 15 supported linkage peaks were cross-validated between 2 different ethnic groups, and 2 peaks on chromosomal region 1q31 and 16p11 were validated in 3 ethnic groups. In conclusion, this investigation demonstrates that genetic effects on blood pressure vary by age. The improved genetic linkage results presented here should help to identify the specific genetic variants that explain the observed results.

Whole-genome approach implicates CD44 in cellular resistance to carboplatin

Carboplatin is a chemotherapeutic agent used in the management of many cancers, yet treatment is limited by resistance and toxicities. To achieve a better understanding of the genetic contribution to carboplatin resistance or toxicities, lymphoblastoid cell lines from 34 large Centre d'Etude du Polymorphisme Humain pedigrees were utilised to evaluate interindividual variation in carboplatin cytotoxicity. Significant heritability, ranging from 0.17-0.36 (p = 1 × 10-7 to 9 × 10-4), was found for cell growth inhibition following 72-hour treatment at each carboplatin concentration (10, 20, 40 and 80 μM) and IC50 (concentration for 50 per cent cell growth inhibition). Linkage analysis revealed 11 regions with logarithm of odds (LOD) scores greater than 1.5. The highest LOD score on chromosome 11 (LOD = 3.36, p = 4.2 × 10-5) encompasses 65 genes within the 1 LOD confidence interval for the carboplatin IC50. We further analysed the IC50 phenotype with a linkage-directed association analysis using 71 unrelated HapMap and Perlegen cell lines and identified 18 single nucleotide polymorphisms within eight genes that were significantly associated with the carboplatin IC50 (p < 3.6 × 10-5; false discovery rate < 5 per cent). Next, we performed linear regression on the baseline expression and carboplatin IC50 values of the eight associated genes, which identified the most significant correlation between CD44 expression and IC50 (r2 = 0.20; p = 6 × 10-4). The quantitative real-time polymerase chain reaction further confirmed a statistically significant difference in CD44 expression levels between carboplatin-resistant and -sensitive cell lines (p = 5.9 × 10-3). Knockdown of CD44 expression through small interfering RNA resulted in increased cellular sensitivity to carboplatin (p < 0.01). Our whole-genome approach using molecular experiments identified CD44 as being important in conferring cellular resistance to carboplatin.

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Cisplatin is a widely used chemotherapeutic agent; however, nephrotoxicity and neuropathy are obstacles for drug efficacy. Little is known about the genes or genetic variants contributing to the risk of developing these toxicities or chemotherapeutic response. Thus, we have applied a cell-based model to identify and characterize previously unknown genes that may be involved in cellular susceptibility to cisplatin. Lymphoblastoid cell lines from 27 large Centre d'Etude du Polymorphisme Humain pedigrees were used to elucidate the genetic contribution to cisplatin-induced cytotoxicity. Phenotype was defined as cell growth inhibition following exposure of cell lines to increasing concentrations of cisplatin for 48 h. Significant heritability, ranging from 0.32 to 0.43 (P<10), was found for the cytotoxic effects of each concentration (1, 2.5, 5, 10, and 20 micromol/l) and IC50, the concentration required for 50% cell growth inhibition. Linkage analysis revealed 11 genomic regions on six chromosomes with logarithm of odds (LOD) scores above 1.5 for cytotoxic phenotypes. The highest LOD score was found on chromosome 4q21.3-q35.2 (LOD=2.65, P=2.4x10(-4)) for 5 micromol/l cisplatin. Quantitative transmission disequilibrium tests were performed using 191973 nonredundant single nucleotide polymorphisms (SNPs) located in the 1 LOD confidence interval of these 11 regions. Twenty SNPs, with 10 SNPs located in five genes, were significantly associated with cisplatin-induced cytotoxicity (P<or=1x10(-4)). Four of these 20 SNPs were found to explain over 10% of the variation in cisplatin-induced apoptosis. Our results suggest that genetic factors involved in cytotoxicity also contribute to cisplatin-induced apoptosis. These cell lines provide a paradigm to identify previously unknown pharmacogenetic variants associated with drug cytotoxicity.

Genome-Wide Scan for Blood Pressure in Australian and Dutch Subjects Suggests Linkage at 5P, 14Q, and 17P

Large-scale studies estimate the heritability of blood pressure at approximately 50%. We carried out a genome-wide linkage analysis to search for chromosomal loci that might explain this heritability using longitudinal, multiple measures of systolic and diastolic blood pressure obtained in sibling pairs and dizygotic twin pairs from 2 countries (a total of 286 pairs from Australia and 636 pairs from the Netherlands). These pairs and a large number of their parents were genotyped with microsatellite markers. Multivariate linkage analysis of the combined data of both countries, using a variance components approach, showed suggestive linkage for diastolic blood pressure on chromosomes 5p13.1 (logarithm of odds score: 2.48), 14q12 (logarithm of odds score: 2.40) and 17q24.3 (logarithm of odds score: 2.36). The highest logarithm of odds score of 1.21 for systolic blood pressure was observed on chromosome 13q34. These results replicate earlier findings and add to a slowly emerging picture of multiple loci contributing to quantitative blood pressure variation.

Combination of Linkage and Association Studies for Brain Arteriovenous Malformation

Genetic factors for brain arteriovenous malformation are unexplored because of the low incidence of familial cases, albeit local and familial clustering. We used a combination of a linkage study and an association study to explore the genetic background. A genome-wide linkage analysis was performed in 12 patients from 6 unrelated families using the GENEHUNTER program. A genome-wide association analysis of 26 cases and 30 controls was performed using a GeneChip 10K mapping array. Significance levels for linkage and single single-nucleotide polymorphism association analyses were set at P<0.05 and P<0.0001, respectively. Genotyping was also performed using 58 960 single-nucleotide polymorphisms for 2 sets of discordant twins. The linkage analysis revealed 7 candidate regions, with the highest logarithm of odds score of 1.88 (P=0.002) at chromosome 6q25. A significant association was observed for 4 single-nucleotide polymorphisms and 2 haplotypes, but none of them overlapped with candidate linkage regions. Genotyping of the twins showed no genetic heterogeneity. The present study failed to identify genetic factors for arteriovenous malformation although the low statistical power may have resulted in such evidence being missed.

Genome-Wide Linkage Mapping for Valve Calcification Susceptibility Loci in Hypertensive Sibships

It remains unclear whether genetic factors contribute to the susceptibility to valve calcification. Accordingly, echocardiograms and genotyping were performed in 1871 hypertensive siblings who participated in the Hypertension Genetic Epidemiology Network Study. Genome-wide affected sibpair nonparametric linkage analysis was conducted using the allele-sharing method implemented in the Merlin computer program. A total of 1014 sibships from 858 families were evaluated for aortic valve sclerosis or mitral annular calcification. Of these, 78 sibships from 68 families contained > or =2 affected siblings with > or =1 type of valve calcification (142 affected siblings). All 3 of the traits showed a modest degree of familial aggregation, with sibling recurrence risk (SD) and sibling recurrence risk ratio (95% CI) being 0.25 (0.035) and 2.31 (1.72 to 3.11) for aortic valve sclerosis, 0.25 (0.035) and 1.78 (1.36 to 2.33) for mitral annular calcification, and 0.31 (0.030) and 1.52 (1.24 to 1.85) for aortic valve sclerosis and mitral annular calcification, respectively. Affected sibpair linkage analysis revealed the highest logarithm of odds score (3.14) in chromosome 16 at 105.6 cM for aortic valve sclerosis. Other chromosomal regions with logarithm of odds score > or =1.9 were found in chromosomes 19 (2.88), 16 (2.63), 1 (2.12), and 2 (2.03) for aortic valve sclerosis and chromosome 13 (2.12) for any valve calcification. There was no logarithm of odds score > or =1.9 for mitral annular calcification. Our study shows strong linkage of aortic valve sclerosis to chromosome 16q22.1-q22.3 and suggestive linkage to chromosome 19p13.11-p11 and identifies several other promising genomic regions that may contain specific susceptibility loci for valve calcification.

Interstitial cystitis and panic disorder: a potential genetic syndrome.

Evidence from a genetic linkage study had suggested a possible syndrome in some families with panic disorder (PD). This syndrome includes bladder problems (possibly urinary interstitial cystitis [IC]), thyroid disorders, chronic headaches/migraine, and/or mitral valve prolapse. In 19 multiplex families with PD, one marker (D13S779) on chromosome 13 gave a logarithm of odds score of more than 4 when individuals with any of the syndrome conditions were analyzed as affected. Families with the bladder problems yielded the highest logarithm of odds scores. These findings were replicated in an extended sample of 60 families. Whereas PD had been well characterized by direct interview, the urologic problems had been found only via medical history checklists and records. A case review by a board-certified urologist suggested they could be IC. To determine whether patients diagnosed as having IC by urodynamics and/or cystoscopy and their first-degree relatives (FDRs) have increased rates of the syndrome conditions, thus validating that the bladder problems observed in the linkage study could be IC and providing further support for the panic syndrome. Case-control and family history study. Two metropolitan urology clinics. One hundred forty-six probands (67 with IC and 79 with other urologic disorders) and 815 FDRs. Lifetime rates of syndrome conditions in probands and FDRs who were blind to urologic or psychiatric diagnoses in the proband. Compared with patients without IC, patients with IC had a significantly higher lifetime prevalence of PD (controlling for age and sex) (odds ratio, 4.05; 95% confidence interval, 1.22-13.40; P =.02) and a higher lifetime prevalence of any of the syndrome disorders (controlling for age and sex) (odds ratio, 2.22; 95% confidence interval, 0.89-5.54; P =.09). First-degree relatives of probands with (vs without) IC were significantly more likely to have PD, thyroid disorder, urologic problems, and any of the syndrome disorders (controlling for age and sex of the relative and sex of the proband) (adjusted odds ratio, 1.95; 95% confidence interval, 1.13-3.38; P =.02). These results in relatives were not influenced by PD in probands, and did not change substantially when controlling for the proband-relative relationship, modeling age as a categorical (vs continuous) variable, or excluding FDRs with PD. There were no interactions between proband IC status and sex of the relative. The increased frequency of seemingly disparate disorders in patients with IC and their FDRs is consistent with the genetic linkage findings in families with PD. These findings suggest that the bladder problems observed in the linkage study may be IC. The hypothesis that there is a familial, possibly pleiotropic, syndrome that may include IC, PD, thyroid disorders, and other disorders of possible autonomic or neuromuscular control deserves further investigation.