Retinal Vascular Fractal Dimension,Childhood IQ,and Cognitive Ability in Old Age: The Lothian Birth Cohort Study 1936

Purpose

Cerebral microvascular disease is associated with dementia. Differences in the topography of the retinal vascular network may be a marker for cerebrovascular disease. The association between cerebral microvascular state and non-pathological cognitive ageing is less clear, particularly because studies are rarely able to adjust for pre-morbid cognitive ability level. We measured retinal vascular fractal dimension (D _f) as a potential marker of cerebral microvascular disease. We examined the extent to which it contributes to differences in non-pathological cognitive ability in old age, after adjusting for childhood mental ability.

Methods

Participants from the Lothian Birth Cohort 1936 Study (LBC1936) had cognitive ability assessments and retinal photographs taken of both eyes aged around 73 years (n = 648). IQ scores were available from childhood. Retinal vascular D _f was calculated with monofractal and multifractal analysis, performed on custom-written software. Multiple regression models were applied to determine associations between retinal vascular D _f and general cognitive ability (g), processing speed, and memory.

Results

Only three out of 24 comparisons (two eyes × four D _f parameters × three cognitive measures) were found to be significant. This is little more than would be expected by chance. No single association was verified by an equivalent association in the contralateral eye.

Conclusions

The results show little evidence that fractal measures of retinal vascular differences are associated with non-pathological cognitive ageing.     

Replication study of candidate genes for cognitive abilities: the Lothian Birth Cohort 1936

As the proportion of older people in societies has increased, research into the determinants of cognitive ageing has risen in importance. Genetic influences account for over 50% of the variance in adult cognitive abilities. Previous studies on cognition and illnesses with cognitive impairments have identified single nucleotide polymorphisms ( SNPs) within candidate genes that might influence cognition or age-related cognitive change. This study investigated 10 candidate genes in over 1000 Scots: the Lothian Birth Cohort 1936 (LBC1936). These participants were tested on general cognitive ability (Scottish Mental Survey 1947) at age 11. At mean age 70, they completed the same general cognitive ability test and a battery of diverse cognitive tests. Nineteen SNPs in 10 genes previously associated with cognition, Alzheimer's disease or autism were genotyped in 1063 individuals. The genes include BDNF, COMT, DISC1, KL, NCSTN, PPP1R1B, PRNP, SHANK3, SORL1 and WRN . Linear regression analysis investigated the additive effect of each SNP on the cognitive variables, covarying for gender and age. Childhood cognitive ability was also included as a covariate to identify associations specifically with cognitive ageing. Certain SNPs reached the conventional significance threshold for association with cognitive traits or cognitive ageing in LBC1936 ( P   <   0.05). No SNPs reached the Bonferroni-level of significance (all P   >   0.0015). Of the 10 genes, we discuss that COMT , KL , PRNP, PPP1R1B, SORL1 and WRN especially merit further attention for association with cognitive ability and/or age-related cognitive change. All results are also presented so that they are valuable for future meta-analyses of candidate genes for cognition.     

Identification of novel genetic susceptibility loci for Behçet's disease using a genome-wide association study

Introduction

Behçet's disease is a chronic systemic inflammatory disease that remains incompletely understood. Herein, we perform the first genome-wide association study in Behçet's disease.

Methods

Using DNA pooling technology and the Affymetrix 500K arrays, we identified possible candidate gene associations with Behçet's disease in a cohort of 152 Behçet's disease patients and 172 healthy ethnically matched controls. Genetic loci that were identified in the pooling study were genotyped in patients and controls using TaqMan genotyping technology.

Results

We identified genetic associations between Behçet's disease and single-nucleotide polymorphisms (SNPs) in KIAA1529, CPVL, LOC100129342, UBASH3B, and UBAC2 (odds ratio = 2.04, 2.26, 1.84, 1.71, and 1.61, respectively; P value = 4.2 × 10^-5, 1.0 × 10^-4, 3.0 × 10^-4, 1.5 × 10^-3, and 5.8 × 10^-3, respectively). Among the associated SNPs, the Behçet's disease-risk allele in rs2061634 leads to substitution of serine to cysteine at amino acid position 995 (S995C) in the KIAA1529 protein.

Conclusions

Using an unbiased whole-genome genetic association approach, we identified novel candidate genetic loci that are associated with increased susceptibility for Behçet's disease. These findings will help to better understand the pathogenesis of Behçet's disease and identify novel targets for therapeutic intervention.     

Early gene expression changes with rush immunotherapy

Background

Allergic rhinitis (AR) affects up to 80% of children with asthma and increases asthma severity. Thymic stromal lymphopoietin (TSLP) is a key mediator of allergic inflammation. The role of the TSLP gene (TSLP) in the pathogenesis of AR has not been studied.

Objective

To test for associations between variants in TSLP, TSLP -related genes, and AR in children with asthma.

Methods

We genotyped 15 single nucleotide polymorphisms (SNPs) in TSLP, OX40L, IL7R, and RXRα in three independent cohorts: 592 asthmatic Costa Rican children and their parents, 422 nuclear families of North American children with asthma, and 239 Swedish children with asthma. We tested for associations between these SNPs and AR. As we previously reported sex-specific effects for TSLP, we performed overall and sex-stratified analyses. We additionally performed secondary analyses for gene-by-gene interactions.

Results

Across the three cohorts, the T allele of TSLP SNP rs1837253 was undertransmitted in boys with AR and asthma as compared to boys with asthma alone. The SNP was associated with reduced odds for AR (odds ratios ranging from 0.56 to 0.63, with corresponding Fisher's combined P value of 1.2 × 10^-4). Our findings were significant after accounting for multiple comparisons. SNPs in OX40L, IL7R, and RXRα were not consistently associated with AR in children with asthma. There were nominally significant interactions between gene pairs.

Conclusions

TSLP SNP rs1837253 is associated with reduced odds for AR in boys with asthma. Our findings support a role for TSLP in the pathogenesis of AR in children with asthma.     

A high-resolution linkage map of the Rfd1, a restorer-of-fertility locus for cytoplasmic male sterility in radish (Raphanus sativus L.) produced by a combination of bulked segregant analysis and RNA-Seq

Key message

We utilized a combination of BSA and RNA-Seq to identify SNPs linked to the Rfd1 locus, a restorer-of-fertility gene in radish. A high-density linkage map was constructed using this approach.

Abstract

Male fertility of cytoplasmic male sterility conditioned by the Dongbu cytoplasmic and genic male-sterility cytoplasm can be restored by a restorer-of-fertility locus, Rfd1, in radish. To construct a high-density linkage map and to identify a candidate gene for the Rfd1 locus, bulked segregant analysis and RNA-seq approaches were combined. A total of 26 and 28 million reads produced from male-fertile and male-sterile bulked RNA were mapped to the radish reference unigenes. After stringent screening of SNPs, 327 reliable SNPs of 109 unigenes were selected. Arabidopsis homologs for 101 of the 109 genes were clustered around the 4,000 kb region of Arabidopsis chromosome 3, which was syntenic to the Rfd1 flanking region. Since the reference unigene set was incomplete, the contigs were de novo assembled to identify 134 contigs harboring SNPs. Most of SNP-containing contigs were also clustered on the same syntenic region in Arabidopsis chromosome. A total of 21 molecular markers positioned within a 2.1 cM interval including the Rfd1 locus were developed, based on the selected unigenes and contigs. A segregating population consisting of 10,459 individuals was analyzed to identify recombinants containing crossovers within this interval. A total of 284 identified recombinants were then used to construct a high-density map, which delimited the Rfd1 locus into an 83-kb syntenic interval of Arabidopsis chromosome 3. Since no candidate gene, such as a pentatricopeptide repeat (PPR)-coding gene, was found in this interval, 231 unigenes and 491 contigs containing putative PPR motifs were analyzed further, but no PPR gene in linkage disequilibrium with the Rfd1 locus could be found.     

Analysis of IL-12 p40 subunit gene and IFN-γ G5644A polymorphisms in Idiopathic Pulmonary Fibrosis

Background

Genes encoding cytokine mediators are prime candidates for genetic analysis in conditions with T-helper (Th) cell disease driven imbalance. Idiopathic Pulmonary Fibrosis (IPF) is a predominantly Th2 mediated disease associated with a paucity of interferon-gamma (IFN-γ). The paucity of IFN-γ may favor the development of progressive fibrosis in IPF. Interleukin-12 (IL-12) plays a key role in inducing IFN-γ production. The aim of the current study was to assess whether the 1188 (A/C) 3'UTR single nucleotide polymorphism (SNP) in the IL-12 p40 subunit gene which was recently found to be functional and the 5644 (G/A) 3' UTR SNP of the IFN-γ gene were associated with susceptibility to IPF.

Methods

We investigated the allelic distribution in these loci in UK white Caucasoid subjects comprising 73 patients with IPF and 157 healthy controls. The SNPs were determined using the polymerase chain reaction in association with sequence-specific primers incorporating mismatches at the 3'-end.

Results

Our results showed that these polymorphisms were distributed similarly in the IPF and control groups

Conclusion

We conclude that these two potentially important candidate gene single nucleotide polymorphisms are not associated with susceptibility to IPF.     

From multidimensional neuropsychological outcomes to a cognitive complication rate: The International Subarachnoid Aneurysm Trial

Background

The neuropsychological arm of the International Subarachnoid Aneurysm Trial (N-ISAT) evaluated the cognitive outcome of 573 patients at 12 months following subarachnoid haemorrhage (SAH). The assessment included 29 psychometric measures, yielding a substantial and complex body of data. We have explored alternative and optimal methodologies for analysing and summarising these data to enable the estimation of a cognitive complication rate (CCR). Any differences in cognitive outcome between the two arms of the trial are not however reported here.

Methods

All individual test scores were transformed into z-scores and a 5^th percentile cut-off for impairment was established. A principal components analysis (PCA) was applied to these data to mathematically transform correlated test scores into a smaller number of uncorrelated principal components, or cognitive 'domains'. These domains formed the basis for grouping and weighting individual patients' impaired scores on individual measures. In order to increase the sample size, a series of methods for handling missing data were applied.

Results

We estimated a 34.1% CCR in all those patients seen face-to-face, rising to 37.4% CCR with the inclusion of patients who were unable to attend assessment for reason related to the index SAH. This group demonstrated significantly more self and carer/relative rated disability on a Health Related Quality of Life questionnaire, than patients classified as having no functionally significant cognitive deficits.

Conclusion

Evaluating neuropsychological outcome in a large RCT involves unique methodological and organizational challenges. We have demonstrated how these problems may be addressed by re-classifying interval data from 29 measures into a dichotomous CCR. We have presented a 'sliding scale' of undifferentiated individual cognitive impairments, and then on the basis of PCA-derived cognitive 'domains', included consideration of the distribution of impairments in these terms. In order to maximize sample size we have suggested ways for patients who did not complete the entire protocol to be included in the overall CCR.

ISAT trial registration

ISRCTN49866681     

TLR7 single-nucleotide polymorphisms in the 3' untranslated region and intron 2 independently contribute to systemic lupus erythematosus in Japanese women: a case-control association study

Introduction

The Toll-like receptor 7 (TLR7) gene, encoded on human chromosome Xp22.3, is crucial for type I interferon production. A recent multicenter study in East Asian populations, comprising Chinese, Korean and Japanese participants, identified an association of a TLR7 single-nucleotide polymorphism (SNP) located in the 3' untranslated region (3' UTR), rs3853839, with systemic lupus erythematosus (SLE), especially in males, although some difference was observed among the tested populations. To test whether additional polymorphisms contribute to SLE in Japanese, we systematically analyzed the association of TLR7 with SLE in a Japanese female population.

Methods

A case-control association study was conducted on eight tag SNPs in the TLR7 region, including rs3853839, in 344 Japanese females with SLE and 274 healthy female controls.

Results

In addition to rs3853839, two SNPs in intron 2, rs179019 and rs179010, which were in moderate linkage disequilibrium with each other (r ² = 0.53), showed an association with SLE (rs179019: P = 0.016, odds ratio (OR) 2.02, 95% confidence interval (95% CI) 1.15 to 3.54; rs179010: P = 0.018, OR 1.75, 95% CI 1.10 to 2.80 (both under the recessive model)). Conditional logistic regression analysis revealed that the association of the intronic SNPs and the 3' UTR SNP remained significant after we adjusted them for each other. When only the patients and controls carrying the risk genotypes at the 3' UTR SNPpositionwere analyzed, the risk of SLE was significantly increased when the individuals also carried the risk genotypes at both of the intronic SNPs (P = 0.0043, OR 2.45, 95% CI 1.31 to 4.60). Furthermore, the haplotype containing the intronic risk alleles in addition to the 3' UTR risk allele was associated with SLE under the recessive model (P = 0.016, OR 2.37, 95% CI 1.17 to 4.80), but other haplotypes were not associated with SLE.

Conclusions

The TLR7 intronic SNPs rs179019 and rs179010 are associated with SLE independently of the 3' UTR SNP rs3853839 in Japanese women. Our findings support a role of TLR7 in predisposition for SLE in Asian populations.     

An extensive analysis of the African rice genetic diversity through a global genotyping

Key message

We present here the first curated collection of wild and cultivated African rice species. For that, we designed specific SNPs and were able to structure these very low diverse species.

Abstract

Oryza glaberrima, the cultivated African rice, is endemic from Africa. This species and its direct ancestor, O. barthii, are valuable tool for improvement of Asian rice O. sativa in terms of abiotic and biotic stress resistance. However, only a few limited studies about the genetic diversity of these species were performed. In the present paper, and for the first time at such extend, we genotyped 279 O. glaberrima, selected both for their impact in current breeding and for their geographical distribution, and 101 O. barthii, chosen based on their geographic origin, using a set of 235 SNPs specifically designed for African rice diversity. Using those data, we were able to structure the individuals from our sample in three populations for O. barthii, related to geography, and two populations in O. glaberrima; these two last populations cannot be linked however to any currently phenotyped trait. Moreover, we were also able to identify misclassification in O. glaberrima as well as in O. barthii and identified new form of O. sativa from the set of African varieties.     

Exome sequencing reveals a novel TTC19 mutation in an autosomal recessive spinocerebellar ataxia patient

Background

Genetic modifiers are important clues for the identification of therapeutic targets in neurodegenerative diseases. Huntington disease (HD) is one of the most common autosomal dominant inherited neurodegenerative diseases. The clinical symptoms include motor abnormalities, cognitive decline and behavioral disturbances. Symptom onset is typically between 40 and 50 years of age, but can vary by several decades in extreme cases and this is in part determined by modifying genetic factors. The metabolic master regulator PGC-1α, coded by the PPARGC1A gene, coordinates cellular respiration and was shown to play a role in neurodegenerative diseases, including HD.

Methods

Using a candidate gene approach we analyzed a large European cohort (n?=?1706) from the REGISTRY study for associations between PPARGC1A genotype and age at onset (AO) in HD.

Results

We report that a coding variant (rs3736265) in PPARGC1A is associated with an earlier motor AO in men but not women carrying the HD mutation.

Conclusions

These results further strengthen the evidence for a role of PGC-1α in HD and unexpectedly suggest a gender effect.     

Cognitive function in childhood and lifetime cognitive change in relation to mental wellbeing in four cohorts of older people

Background

Poorer cognitive ability in youth is a risk factor for later mental health problems but it is largely unknown whether cognitive ability, in youth or in later life, is predictive of mental wellbeing. The purpose of this study was to investigate whether cognitive ability at age 11 years, cognitive ability in later life, or lifetime cognitive change are associated with mental wellbeing in older people.

Methods

We used data on 8191 men and women aged 50 to 87 years from four cohorts in the HALCyon collaborative research programme into healthy ageing: the Aberdeen Birth Cohort 1936, the Lothian Birth Cohort 1921, the National Child Development Survey, and the MRC National Survey for Health and Development. We used linear regression to examine associations between cognitive ability at age 11, cognitive ability in later life, and lifetime change in cognitive ability and mean score on the Warwick Edinburgh Mental Wellbeing Scale and meta-analysis to obtain an overall estimate of the effect of each.

Results

People whose cognitive ability at age 11 was a standard deviation above the mean scored 0.53 points higher on the mental wellbeing scale (95% confidence interval 0.36, 0.71). The equivalent value for cognitive ability in later life was 0.89 points (0.72, 1.07). A standard deviation improvement in cognitive ability in later life relative to childhood ability was associated with 0.66 points (0.39, 0.93) advantage in wellbeing score. These effect sizes equate to around 0.1 of a standard deviation in mental wellbeing score. Adjustment for potential confounding and mediating variables, primarily the personality trait neuroticism, substantially attenuated these associations.

Conclusion

Associations between cognitive ability in childhood or lifetime cognitive change and mental wellbeing in older people are slight and may be confounded by personality trait differences.     

The BRCA1 Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies

Background

We studied linkage disequilibrium (LD) patterns at the BRCA1 locus, a susceptibility gene for breast and ovarian cancer, using a dense set of 114 single nucleotide polymorphisms in 5 population groups. We focused on Ashkenazi Jews in whom there are known founder mutations, to address the question of whether we would have been able to identify the 185delAG mutation in a case-control association study (should one have been done) using anonymous genetic markers. This mutation is present in approximately 1% of the general Ashkenazi population and 4% of Ashkenazi breast cancer cases. We evaluated LD using pairwise and haplotype-based methods, and assessed correlation of SNPs with the founder mutations using Pearson's correlation coefficient.

Results

BRCA1 is characterized by very high linkage disequilibrium in all populations spanning several hundred kilobases. Overall, haplotype blocks and pair-wise LD bins were highly correlated, with lower LD in African versus non-African populations. The 185delAG and 5382insC founder mutations occur on the two most common haplotypes among Ashkenazim. Because these mutations are rare, even though they are in strong LD with many other SNPs in the region as measured by D-prime, there were no strong associations when assessed by Pearson's correlation coefficient, r (maximum of 0.04 for the 185delAG).

Conclusion

Since the required sample size is related to the inverse of r, this suggests that it would have been difficult to map BRCA1 in an Ashkenazi case-unrelated control association study using anonymous markers that were linked to the founder mutations.     

Rare allele of HvLox-1 associated with lipoxygenase activity in barley (Hordeum vulgare L.)

Key message

Identification and allele-specific marker development of a functional SNP of HvLox - 1 which associated with barley lipoxygenase activity.

Abstract

Improving the stability of the flavor of beer is one of the main objectives in breeding barley for malting, and lipoxygenase-1 (LOX-1) is a key enzyme controlling this trait. In this study, a modified LOX activity assay was used for null LOX-1 mutant screening. Four barley landraces with no detected level of LOX-1 activity were screened from 1,083 barley germplasm accessions from China. The genomic sequence diversity of the HvLox-1 gene of the four null LOX-1 Chinese landraces was compared with that of a further 76 accessions. A total of 104 nucleotide polymorphisms were found, which contained 83 single-nucleotide polymorphisms (SNPs), 7 multiple-nucleotide polymorphisms, and 14 insertions and deletions. Most notably, we found a rare C/G mutation (SNP-61) in the second intron which led to null LOX-1 activity through an altered splicing acceptor site. In addition, an allele-specific polymerase chain reaction marker was developed for the genotyping of SNP-61, which could be used in breeding programs for barley to be used for malting. The objective was to improve beer quality.     

Genotyping panel for assessing response to cancer chemotherapy

Background

Variants in numerous genes are thought to affect the success or failure of cancer chemotherapy. Interindividual variability can result from genes involved in drug metabolism and transport, drug targets (receptors, enzymes, etc), and proteins relevant to cell survival (e.g., cell cycle, DNA repair, and apoptosis). The purpose of the current study is to establish a flexible, cost-effective, high-throughput genotyping platform for candidate genes involved in chemoresistance and -sensitivity, and treatment outcomes.

Methods

We have adopted SNPlex for genotyping 432 single nucleotide polymorphisms (SNPs) in 160 candidate genes implicated in response to anticancer chemotherapy.

Results

The genotyping panels were applied to 39 patients with chronic lymphocytic leukemia undergoing flavopiridol chemotherapy, and 90 patients with colorectal cancer. 408 SNPs (94%) produced successful genotyping results. Additional genotyping methods were established for polymorphisms undetectable by SNPlex, including multiplexed SNaPshot for CYP2D6 SNPs, and PCR amplification with fluorescently labeled primers for the UGT1A1 promoter (TA)nTAA repeat polymorphism.

Conclusion

This genotyping panel is useful for supporting clinical anticancer drug trials to identify polymorphisms that contribute to interindividual variability in drug response. Availability of population genetic data across multiple studies has the potential to yield genetic biomarkers for optimizing anticancer therapy.     

Genome re-sequencing suggested a weedy rice origin from domesticated indica-japonica hybridization: a case study from southern China

Main conclusion

Whole-genome re-sequencing of weedy rice from southern China reveals that weedy rice can originate from hybridization of domesticated indica and japonica rice.

Abstract

Weedy rice (Oryza sativa f. spontanea Rosh.), which harbors phenotypes of both wild and domesticated rice, has become one of the most notorious weeds in rice fields worldwide. While its formation is poorly understood, massive amounts of rice genomic data may provide new insights into this issue. In this study, we determined genomes of three weedy rice samples from the lower Yangtze region, China, and investigated their phylogenetics, population structure and chromosomal admixture patterns. The phylogenetic tree and principle component analysis based on 46,005 SNPs with 126 other Oryza accessions suggested that the three weedy rice accessions were intermediate between japonica and indica rice. An ancestry inference study further demonstrated that weedy rice had two dominant genomic components (temperate japonica and indica). This strongly suggests that weedy rice originated from indica-japonica hybridization. Furthermore, 22,443 novel fixed single nucleotide polymorphisms were detected in the weedy genomes and could have been generated after indica-japonica hybridization for environmental adaptation.     

Transcriptome analysis reveals absence of unintended effects in drought-tolerant transgenic plants overexpressing the transcription factor ABF3

Background

The superfamily of ABC proteins is among the largest known in nature. Its members are mainly, but not exclusively, involved in the transport of a broad range of substrates across biological membranes. Many contribute to multidrug resistance in microbial pathogens and cancer cells. The diversity of ABC proteins in fungi is comparable with those in multicellular animals, but so far fungal ABC proteins have barely been studied.

Results

We performed a phylogenetic analysis of the ABC proteins extracted from the genomes of 27 fungal species from 18 orders representing 5 fungal phyla thereby covering the most important groups. Our analysis demonstrated that some of the subfamilies of ABC proteins remained highly conserved in fungi, while others have undergone a remarkable group-specific diversification. Members of the various fungal phyla also differed significantly in the number of ABC proteins found in their genomes, which is especially reduced in the yeast S. cerevisiae and S. pombe.

Conclusions

Data obtained during our analysis should contribute to a better understanding of the diversity of the fungal ABC proteins and provide important clues about their possible biological functions.     

Investigation of Caucasian rheumatoid arthritis susceptibility loci in African patients with the same disease

Introduction

The largest genetic risk to develop rheumatoid arthritis (RA) arises from a group of alleles of the HLA DRB1 locus ('shared epitope', SE). Over 30 non-HLA single nucleotide polymorphisms (SNPs) predisposing to disease have been identified in Caucasians, but they have never been investigated in West/Central Africa. We previously reported a lower prevalence of the SE in RA patients in Cameroon compared to European patients and aimed in the present study to investigate the contribution of Caucasian non-HLA RA SNPs to disease susceptibility in Black Africans.

Methods

RA cases and controls from Cameroon were genotyped for Caucasian RA susceptibility SNPs using Sequenom MassArray technology. Genotype data were also available for 5024 UK cases and 4281 UK controls and for 119 Yoruba individuals in Ibadan, Nigeria (YRI, HapMap). A Caucasian aggregate genetic-risk score (GRS) was calculated as the sum of the weighted risk-allele counts.

Results

After genotyping quality control procedures were performed, data on 28 Caucasian non-HLA susceptibility SNPs were available in 43 Cameroonian RA cases and 44 controls. The minor allele frequencies (MAF) were tightly correlated between Cameroonian controls and YRI individuals (correlation coefficient 93.8%, p = 1.7E-13), and they were pooled together. There was no correlation between MAF of UK and African controls; 13 markers differed by more than 20%. The MAF for markers at PTPN22, IL2RA, FCGR2A and IL2/IL21 was below 2% in Africans. The GRS showed a strong association with RA in the UK. However, the GRS did not predict RA in Africans (OR = 0.71, 95% CI 0.29 - 1.74, p = 0.456). Random sampling from the UK cohort showed that this difference in association is unlikely to be explained by small sample size or chance, but is statistically significant with p<0.001.

Conclusions

The MAFs of non-HLA Caucasian RA susceptibility SNPs are different between Caucasians and Africans, and several polymorphisms are barely detectable in West/Central Africa. The genetic risk of developing RA conferred by a set of 28 Caucasian susceptibility SNPs is significantly different between the UK and Africa with p<0.001. Taken together, these observations strengthen the hypothesis that the genetic architecture of RA susceptibility is different in different ethnic backgrounds.     

Use of synteny to identify candidate genes underlying QTL controlling stomatal traits in faba bean (Vicia faba L.)

Key message

We have identified QTLs for stomatal characteristics on chromosome II of faba bean by applying SNPs derived from M. truncatula , and have identified candidate genes within these QTLs using synteny between the two species.

Abstract

Faba bean (Vicia faba L.) is a valuable food and feed crop worldwide, but drought often limits its production, and its genome is large and poorly mapped. No information is available on the effects of genomic regions and genes on drought adaptation characters such as stomatal characteristics in this species, but the synteny between the sequenced model legume, Medicago truncatula, and faba bean can be used to identify candidate genes. A mapping population of 211 F₅ recombinant inbred lines (Mélodie/2 × ILB 938/2) were phenotyped to identify quantitative trait loci (QTL) affecting stomatal morphology and function, along with seed weight, under well-watered conditions in a climate-controlled glasshouse in 2013 and 2014. Canopy temperature (CT) was evaluated in 2013 under water-deficit (CTd). In total, 188 polymorphic single nucleotide polymorphisms (SNPs), developed from M. truncatula genome data, were assigned to nine linkage groups that covered ~928 cM of the faba bean genome with an average inter-marker distance of 5.8 cM. 15 putative QTLs were detected, of which eight (affecting stomatal density, length and conductance and CT) co-located on chromosome II, in the vicinity of a possible candidate gene—a receptor-like protein kinase found in the syntenic interval of M. truncatula chromosome IV. A ribose-phosphate pyrophosphokinase from M. truncatula chromosome V, postulated as a possible candidate gene for the QTL for CTd, was found some distance away in the same chromosome. These results demonstrate that genomic information from M. truncatula can successfully be translated to the faba bean genome.     

OsABCG15 encodes a membrane protein that plays an important role in anther cuticle and pollen exine formation in rice

Key message

An ABC transporter gene ( OsABCG15 ) was proven to be involved in pollen development in rice. The corresponding protein was localized on the plasma membrane using subcellular localization.

Abstract

Wax, cutin, and sporopollenin are important for normal development of the anther cuticle and pollen exine, respectively. Their lipid soluble precursors, which are produced in the tapetum, are then secreted and transferred to the anther and microspore surface for polymerization. However, little is known about the mechanisms underlying the transport of these precursors. Here, we identified and characterized a member of the G subfamily of ATP-binding cassette (ABC) transporters, OsABCG15, which is required for the secretion of these lipid-soluble precursors in rice. Using map-based cloning, we found a spontaneous A-to-C transition in the fourth exon of OsABCG15 that caused an amino acid substitution of Thr-to-Pro in the predicted ATP-binding domain of the protein sequence. This osabcg15 mutant failed to produce any viable pollen and was completely male sterile. Histological analysis indicated that osabcg15 exhibited an undeveloped anther cuticle, enlarged middle layer, abnormal Ubisch body development, tapetum degeneration with a falling apart style, and collapsed pollen grains without detectable exine. OsABCG15 was expressed preferentially in the tapetum, and the fused GFP-OsABCG15 protein was localized to the plasma membrane. Our results suggested that OsABCG15 played an essential role in the formation of the rice anther cuticle and pollen exine. This role may include the secretion of the lipid precursors from the tapetum to facilitate the transfer of precursors to the surface of the anther epidermis as well as to microspores.     

Transbronchial biopsy is useful in predicting UIP pattern

Background

The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2). We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency.

Methods

The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV₁ percent of predicted and FEV₁/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD.

Results

Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV₁ percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV₁ percent of predicted and pre-bronchodilator FEV₁/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed.

Conclusions

IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.