Immunochip analysis identifies association of the RAD50/IL13 region with human longevity

Human longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long‐lived individuals (LLI) and 8919 younger controls. First, we performed a large‐scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune‐associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip‐wide significant signal (P_Immunochip = 7.01 × 10^–9) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with P_Immunochip < 5 × 10^–4 for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta‐analysis of the combined French and Danish data after adjusting for multiple testing. In a meta‐analysis of all three samples, rs2706372 reached a P‐value of P_{Immunochip+Repl} = 5.42 × 10^?7 (OR = 1.20; 95% CI = 1.12–1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life.     

Association between METTL3 gene polymorphisms and neuroblastoma susceptibility: A nine‐centre case‐control study

Neuroblastoma ranks as the most commonly seen and deadly solid tumour in infancy. The aberrant activity of m⁶A‐RNA methyltransferase METTL3 is involved in human cancers. Therefore, functional genetic variants in the METTL3 gene may contribute to neuroblastoma risk. In the current nine‐centre case‐control study, we aimed to analyse the association between the METTL3 gene single nucleotide polymorphisms (SNPs) and neuroblastoma susceptibility. We genotyped four METTL3 gene SNPs (rs1061026 T>G, rs1061027 C>A, rs1139130 A>G, and rs1263801 G>C) in 968 neuroblastoma patients and 1814 controls in China. We found significant associations between these SNPs and neuroblastoma risk in neither single‐locus nor combined analyses. Interestingly, in the stratified analysis, we observed a significant risk association with rs1061027 AA in subgroups of children ≤ 18 months of age (adjusted OR = 1.87, 95% CI = 1.03‐3.41, P = .040) and females (adjusted OR = 1.86, 95% CI = 1.07‐3.24, P = .028). Overall, we identified a significant association between METTL3 gene rs1061027 C>A polymorphism and neuroblastoma risk in children ≤18 months of age and females. Our findings provide novel insights into the genetic determinants of neuroblastoma.     

Molecular diversity and landscape genomics of the crop wild relative Triticum urartu across the Fertile Crescent

Modern plant breeding can benefit from the allelic variation that exists in natural populations of crop wild relatives that evolved under natural selection in varying pedoclimatic conditions. In this study, next‐generation sequencing was used to generate 1.3 million genome‐wide single nucleotide polymorphisms (SNPs) on ex situ collections of Triticum urartu L., the wild donor of the A^u subgenome of modern wheat. A set of 75 511 high‐quality SNPs were retained to describe 298 T. urartu accessions collected throughout the Fertile Crescent. Triticum urartu showed a complex pattern of genetic diversity, with two main genetic groups distributed sequentially from west to east. The incorporation of geographical information on sampling points showed that genetic diversity was correlated to the geographical distance (R² = 0.19) separating samples from Jordan and Lebanon, from Syria and southern Turkey, and from eastern Turkey, Iran and Iraq. The wild emmer genome was used to derive the physical positions of SNPs on the seven chromosomes of the A^u subgenome, allowing us to describe a relatively slow decay of linkage disequilibrium in the collection. Outlier loci were described on the basis of the geographic distribution of the T. urartu accessions, identifying a hotspot of directional selection on chromosome 4A. Bioclimatic variation was derived from grid data and related to allelic variation using a genome‐wide association approach, identifying several marker–environment associations (MEAs). Fifty‐seven MEAs were associated with altitude and temperature measures while 358 were associated with rainfall measures. The most significant MEAs and outlier loci were used to identify genomic loci with adaptive potential (some already reported in wheat), including dormancy and frost resistance loci. We advocate the application of genomics and landscape genomics on ex situ collections of crop wild relatives to efficiently identify promising alleles and genetic materials for incorporation into modern crop breeding.     

Genome‐wide association study of osteochondrosis in the tarsocrural joint of Dutch Warmblood horses identifies susceptibility loci on chromosomes 3 and 10

Equine osteochondrosis is a developmental joint disease that is a significant source of morbidity affecting multiple breeds of horse. The genetic variants underlying osteochondrosis susceptibility have not been established. Here, we describe the results of a genome‐wide association study of osteochondrosis using 90 cases and 111 controls from a population of Dutch Warmblood horses. We report putative associations between osteochondrosis and loci on chromosome 3 (BIEC2‐808543; P = 5.03 × 10^?7) and chromosome 10 (BIEC2‐121323; P = 2.62 × 10^?7).     

Novel Y‐chromosome polymorphisms in Chinese domestic yak

Y‐chromosome‐specific haplotypes (Y‐haplotypes) constructed using single nucleotide polymorphisms (Y‐SNPs) in the MSY (male‐specific region of the Y‐chromosome) are valuable in population genetic studies. But sequence variants in the yak MSY region have been poorly characterized so far. In this study, we screened a total of 16 Y‐chromosome‐specific gene segments from the ZFY, SRY, UTY, USP9Y, AMELY and OFD1Y genes to identify Y‐SNPs in domestic yaks. Six novel Y‐SNPs distributed in the USP9Y (g.223C>T), UTY19 (g.158A>C and g.169C>T), AMELY2 (g.261C>T), OFD1Y9 (g.165A>G) and SRY4 (g.104G>A) loci, which can define three Y‐haplotypes (YH1, YH2 and YH3) in yaks, were discovered. YH1 was the dominant and presumably most ancient haplotype based on the comparison of UTY19 locus with other bovid species. Interestingly, we found informative UTY19 markers (g.158A>C and g.169C>T) that can effectively distinguish the three yak Y‐haplotypes. The nucleotide diversity was 1.7 × 10^?4 ± 0.3 × 10^?4, indicating rich Y‐chromosome diversity in yaks. We identified two highly divergent lineages (YH1 and YH2 vs. YH3) that share similar frequencies (YH1 +  YH2: 0.82–0.89, YH3: 0.11–0.18) among all three populations. In agreement with previous mtDNA studies, we supported the hypothesis that the two highly divergent lineages (YH1 and YH2 vs. YH3) derived from a single gene pool, which can be explained by the reunion of at least two paternal populations with the divergent lineages already accumulated before domestication. We estimated a divergence time of 408 110 years between the two divergent lineages, which is consistent with the data from mitochondrial DNA in yaks.     

Genome‐wide screening for DNA variants associated with reading and language traits

Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome‐wide association scan (GWAS) meta‐analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading‐ and language‐related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10^–7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on‐going international efforts to identify genes contributing to reading and language skills.     

Variants in Notch signalling pathway genes,PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

To identify genetic variants in Notch signalling pathway genes that may predict survival of Han Chinese patients with epithelial ovarian cancer (EOC), we analysed a total of 1273 single nucleotide polymorphisms (SNPs) within 75 Notch genes in 480 patients from a published EOC genomewide association study (GWAS). We found that PSEN1 rs165934 and MAML2 rs76032516 were associated with overall survival (OS) of patients by multivariate Cox proportional hazards regression analysis. Specifically, the PSEN1 rs165934 AA genotype was associated with a poorer survival (adjusted hazards ratio [adjHR] = 1.41, 95% CI = 1.07‐1.84, and P = .014), compared with the CC + CA genotype, while MAML2 rs76032516 AA + AC genotypes were associated with a poorer survival (adjHR = 1.58, 95% CI = 1.16‐2.14, P = .004), compared with the CC genotype. The combined analysis of these two SNPs revealed that the death risk increased as the number of unfavourable genotypes increased in a dose‐dependent manner (P_trend < .001). Additionally, the expression quantitative trait loci analysis revealed that the SNP rs165932 in the rs165934 LD block (r² = .946) was associated with expression levels of PSEN1, which might be responsible for the observed association with SNP rs165934. The associations of PSEN1 rs165934 and MAML2 rs76032516 of the Notch signalling pathway genes with OS in Chinese EOC patients are novel findings, which need to be validated in other large and independent studies.     

Polymorphisms in a desaturase 2 ortholog associate with cuticular hydrocarbon and male mating success variation in a natural population of Drosophila serrata

Elucidating the nature of genetic variation underlying both sexually selected traits and the fitness components of sexual selection is essential to understanding the broader consequences of sexual selection as an evolutionary process. To date, there have been relatively few attempts to connect the genetic variance in sexually selected traits with segregating DNA sequence polymorphisms. We set out to address this in a well‐characterized sexual selection system – the cuticular hydrocarbons (CHCs) of Drosophila serrata – using an indirect association study design that allowed simultaneous estimation of the genetic variance in CHCs, sexual fitness and single nucleotide polymorphism (SNP) effects in an outbred population. We cloned and sequenced an ortholog of the D. melanogaster desaturase 2 gene, previously shown to affect CHC biosynthesis in D. melanogaster, and associated 36 SNPs with minor allele frequencies > 0.02 with variance in CHCs and sexual fitness. Three SNPs had significant multivariate associations with CHC phenotype (q‐value < 0.05). At these loci, minor alleles had multivariate effects on CHCs that were weakly associated with the multivariate direction of sexual selection operating on these traits. Two of these SNPs had pleiotropic associations with male mating success, suggesting these variants may underlie responses to sexual selection due to this locus. There were 15 significant male mating success associations (q‐value < 0.1), and interestingly, we detected a nonrandom pattern in the relationship between allele frequency and direction of effect on male mating success. The minor‐frequency allele usually reduced male mating success, suggesting a positive association between male mating success and total fitness at this locus.     

Three‐dimensional (3‐D) fluorescence spectroscopy analysis of the fluorescent dissolved organic matter released by the marine toxic dinoflagellate Alexandrium catenella exposed to metal stress by zinc or lead

We investigated the effects of zinc or lead on growth and on exudation of fluorescent dissolved organic matter (FDOM) by the marine toxic dinoflagellate Alexandrium catenella (Whedon & Kofoid) Balech. The species was exposed to increasing free zinc (1.34 × 10^?7 M–3.98 × 10^?6 M) or lead (5.13 × 10^?9 M–1.82 × 10^?7 M) concentra‐tions. Low metal levels ([Zn²⁺] = 1.34 × 10^?7 M; [Pb²⁺] = 5.13 × 10^?9 M) had no effect on cell growth. Toxic effects were observed from higher metal contamination ([Zn²⁺] = 3.98 × 10^?6 M; [Pb²⁺] = 6.54 × 10^?8 M), as a conversion of vegetative cells into cysts. Analysis of the released FDOM by three‐dimensional (3‐D) fluorescence spectroscopy was achieved, using the parallel factor analysis (PARAFAC). The PARAFAC modeling revealed four components associated with two contributions: one related to the biological activity; the other linked to the organic matter decomposition in the culture medium. The C1 component combined a tryptophan peak and characteristics of humic substances, whereas the C2 component was considered as a tryptophan protein fluorophore. The two others C3 and C4 components were associated with marine organic matter production. Relea‐sed fluorescent substances were induced by low ([Zn²⁺]= 1.34 × 10^?7 M; [Pb²⁺] = 5.13 × 10^?9 M) and moderate ([Zn²⁺] = 6.21 × 10^?7 M; [Pb²⁺] = 2.64× 10^?9 M) metal concentrations, suggesting the activation of cellular mechanisms in response to metal stress, to exudate FDOM that could complex metal cations and reduce their toxicity toward A. catenella cells.     

Time‐specific and pleiotropic quantitative trait loci coordinately modulate stem growth in Populus

In perennial woody plants, the coordinated increase of stem height and diameter during juvenile growth improves competitiveness (i.e. access to light); however, the factors underlying variation in stem growth remain unknown in trees. Here, we used linkage‐linkage disequilibrium (linkage‐LD) mapping to decipher the genetic architecture underlying three growth traits during juvenile stem growth. We used two Populus populations: a linkage mapping population comprising a full‐sib family of 1,200 progeny and an association mapping panel comprising 435 unrelated individuals from nearly the entire natural range of Populus tomentosa. We mapped 311 quantitative trait loci (QTL) for three growth traits at 12 timepoints to 42 regions in 17 linkage groups. Of these, 28 regions encompassing 233 QTL were annotated as 27 segmental homology regions (SHRs). Using SNPs identified by whole‐genome re‐sequencing of the 435‐member association mapping panel, we identified significant SNPs (P ≤ 9.4 × 10^?7) within 27 SHRs that affect stem growth at nine timepoints with diverse additive and dominance patterns, and these SNPs exhibited complex allelic epistasis over the juvenile growth period. Nineteen genes linked to potential causative alleles that have time‐specific or pleiotropic effects, and mostly overlapped with significant signatures of selection within SHRs between climatic regions represented by the association mapping panel. Five genes with potential time‐specific effects showed species‐specific temporal expression profiles during the juvenile stages of stem growth in five representative Populus species. Our observations revealed the importance of considering temporal genetic basis of complex traits, which will facilitate the molecular design of tree ideotypes.     

Late‐onset progressive retinal atrophy in the Gordon and Irish Setter breeds is associated with a frameshift mutation in C2orf71

Progressive retinal atrophy (PRA) in dogs is characterised by the degeneration of the photoreceptor cells of the retina, resulting in vision loss and eventually complete blindness. The condition affects more than 100 dog breeds and is known to be genetically heterogeneous between breeds. Around 14 mutations have now been identified that are associated with PRA in around 49 breeds, but for the majority of breeds the mutation(s) responsible have yet to be identified. Using genome‐wide association with 16 Gordon Setter PRA cases and 22 controls, we identified a novel PRA locus, termed rod–cone degeneration 4 (rcd4), on CFA17 (P_raw = 2.22 × 10^?8, P_genome = 2.00 × 10^?5), where a 3.2‐Mb region was homozygous within cases. A frameshift mutation was identified in C2orf71, a gene located within this region. This variant was homozygous in 19 of 21 PRA cases and was at a frequency of approximately 0.37 in the Gordon Setter population. Approximately 10% of cases in our study (2 of 21) are not associated with this C2orf71 mutation, indicating that PRA in this breed is genetically heterogeneous and caused by at least two mutations. This variant is also present in a number of Irish Setter dogs with PRA and has an estimated allele frequency of 0.26 in the breed. The function of C2orf71 remains unknown, but it is important for retinal development and function and has previously been associated with autosomal recessive retinitis pigmentosa in humans.     

Polymorphisms in the AKT1 and AKT2 genes and oesophageal squamous cell carcinoma risk in an Eastern Chinese population

Ethnic Han Chinese are at high risk of developing oesophageal squamous cell carcinoma (ESCC). Aberrant activation of the AKT signalling pathway is involved in many cancers, including ESCC. Some single nucleotide polymorphisms (SNPs) in genes involved in this pathway may contribute to ESCC susceptibility. We selected five potentially functional SNPs in AKT1 (rs2494750, rs2494752 and rs10138277) and AKT2 (rs7254617 and rs2304186) genes and investigated their associations with ESCC risk in 1117 ESCC cases and 1096 controls in an Eastern Chinese population. None of individual SNPs exhibited an association with ESCC risk. However, the combined analysis of three AKT1 SNPs suggested that individuals carrying one of AKT1 variant genotypes had a decreased ESCC risk [adjusted odds ratio (OR) = 0.60, 95% CI = 0.42–0.87]. Further stratified analysis found that AKT1 rs2294750 SNP was associated with significantly decreased ESCC risk among women (adjusted OR = 0.63, 95% CI = 0.43–0.94) and non‐drinkers (OR = 0.79, 95% CI = 0.64–0.99). Similar protective effects on women (adjusted OR = 0.56, 95% CI = 0.37–0.83) and non‐drinker (adjusted OR = 0.75, 95% CI = 0.60–0.94) were also observed for the combined genotypes of AKT1 SNPs. Consistently, logistic regression analysis indicated significant gene–gene interactions among three AKT1 SNPs (P < 0.015). A three‐AKT1 SNP haplotype (C‐A‐C) showed a significant association with a decreased ESCC risk (adjusted OR = 0.70, 95% CI = 0.52–0.94). Multifactor dimensionality reduction analysis confirmed a high‐order gene–environment interaction in ESCC risk. Overall, we found that three AKT1 SNPs might confer protection against ESCC risk; nevertheless, these effects may be dependent on other risk factors. Our results provided evidence of important gene–environment interplay in ESCC carcinogenesis.     

Validation of genetic polymorphisms on BTA14 associated with carcass trait in a commercial Hanwoo population

The objective of this study was to validate the association of significant SNPs identified from a previous genome‐wide association study with carcass weight (CWT) in a commercial Hanwoo population. We genotyped 13 SNPs located on BTA14 in 867 steers from Korea Hanwoo feedlot bulls. Of these 13 SNPs, five SNPs, namely rs29021868, rs110061498, rs109546980, rs42404006 and rs42303720, were found to be significantly associated (P < 0.001) with CWT. These five significant markers spanned the 24.3 to 29.4 Mb region of BTA14. The most significant marker (rs29021868) for CWT in this study had a 13.07 kg allele substitution effect and accounted for 2.4% of the additive genetic variance in the commercial Hanwoo population. The SNP marker rs109546980 was found to be significantly associated with both CWT (P < 0.001) and eye muscle area (P < 0.001) and could potentially be exploited for marker‐assisted selection in Hanwoo cattle. We also genotyped the ss319607402 variation, which maps to intron2 of PLAG1 gene and which is already reported to be associated with height, to identify any significant association with carcass weight; however, no such association was observed in this Hanwoo commercial population.     

SNPs in SNCA,MCCC1, DLG2, GBF1 and MBNL2 are associated with Parkinson's disease in southern Chinese population

Numerous single nucleotide polymorphisms (SNPs), which have been identified as susceptibility factors for Parkinson's disease (PD) as per genome‐wide association studies, have not been fully characterized for PD patients in China. This study aimed to replicate the relationship between 12 novel SNPs of 12 genes and PD risk in southern Chinese population. Twelve SNPs of 12 genes were detected in 231 PD patients and 249 controls, using the SNaPshot technique. Meta‐analysis was used to assess heterogeneity of effect sizes between this study and published data. The impact of SNPs on gene expression was investigated by analysing the SNP‐gene association in the expression quantitative trait loci (eQTL) data sets. rs8180209 of SNCA (allele model: P = .047, OR = 0.77; additive model: P = .047, OR = 0.77), rs2270968 of MCCC1 (dominant model: P = .024, OR = 1.52), rs7479949 of DLG2 (recessive model; P = .019, OR = 1.52), rs10748818 of GBF1 (additive model: P < .001, OR = 0.37), and rs4771268 of MBNL2 (recessive model: P = .003, OR = 0.48) were replicated to be significantly associated with the increased risk of PD. Noteworthy, a meta‐analysis of previous studies suggested rs8180209, rs2270968, rs7479949 and rs4771268 were in line with those of our cohort. Our study replicated five novel functional SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 could be associated with increased risk of PD in southern Chinese population.     

Candidate gene analysis of osteochondrosis in Spanish Purebred horses

Equine osteochondrosis (OC) is a frequent developmental orthopaedic disease with high economic impact on the equine industry and may lead to premature retirement of the animal as a result of chronic pain and lameness. The genetic background of OC includes different genes affecting several locations; however, these genetic associations have been tested in only one or few populations, lacking the validation in others. The aim of this study was to identify the genetic determinants of OC in the Spanish Purebred horse breed. For that purpose, we used a candidate gene approach to study the association between loci previously implicated in the onset and development of OC in other breeds and different OC locations using radiographic data from 144 individuals belonging to the Spanish Purebred horse breed. Of the 48 polymorphisms analysed, three single nucleotide polymorphisms (SNPs) located in the FAF1, FCN3 and COL1A2 genes were found to be associated with different locations of OC lesions. These data contribute insights into the complex gene networks underlying the multifactorial disease OC, and the associated SNPs could be used in a marker‐assisted selection strategy to improve horse health, welfare and competitive lifespan.     

Population genetic correlates of declining transmission in a human pathogen

Pathogen control programs provide a valuable, but rarely exploited, opportunity to directly examine the relationship between population decline and population genetics. We investigated the impact of an ~12‐fold decline in transmission on the population genetics of Plasmodium falciparum infections (n = 1731) sampled from four clinics on the Thai–Burma border over 10 years and genotyped using 96 genome‐wide SNPs. The most striking associated genetic change was a reduction in the frequency of infections containing multiple parasite genotypes from 63% in 2001 to 14% in 2010 (P = 3 × 10^?15). Two measures of the clonal composition of populations (genotypic richness and the β‐parameter of the Pareto distribution) declined over time as more people were infected by parasites with identical multilocus genotypes, consistent with increased selfing and a reduction in the rate at which multilocus genotypes are broken apart by recombination. We predicted that the reduction in transmission, multiple clone carriage and outbreeding would be mirrored by an increased influence of genetic drift. However, geographical differentiation and expected heterozygosity remained stable across the sampling period. Furthermore, N_e estimates derived from allele frequencies fluctuation between years remained high (582 to ∞) and showed no downward trend. These results demonstrate how genetic data can compliment epidemiological assessments of infectious disease control programs. The temporal changes in a single declining population parallel to those seen in comparisons of parasite genetics in regions of differing endemicity, strongly supporting the notion that reduced opportunity for outbreeding is the key driver of these patterns.     

Profile of common prostate cancer risk variants in an unscreened Romanian population

To find sequence variants affecting prostate cancer (PCA) susceptibility in an unscreened Romanian population we use a genome‐wide association study (GWAS). The study population included 990 unrelated pathologically confirmed PCA cases and 1034 male controls. DNA was genotyped using Illumina SNP arrays, and 24.295.558 variants were imputed using the 1000 Genomes data set. An association test was performed between the imputed markers and PCA. A systematic literature review for variants associated with PCA risk identified 115 unique variants that were tested in the Romanian sample set. Thirty of the previously reported SNPs replicated (P‐value < 0.05), with the strongest associations observed at: 8q24.21, 11q13.3, 6q25.3, 5p15.33, 22q13.2, 17q12 and 3q13.2. The replicated variants showing the most significant association in Romania are rs1016343 at 8q24.21 (P = 2.2 × 10^?4), rs7929962 at 11q13.3 (P = 2.7 × 10^?4) and rs9364554 at 6q25.2 (P = 4.7 × 10^?4). None of the variants tested in the Romanian GWAS reached genome‐wide significance (P‐value <5 × 10^?8) but 807 markers had P‐values <1 × 10^?4. Here, we report the results of the first GWAS of PCA performed in a Romanian population. Our study provides evidence that a substantial fraction of previously validated PCA variants associate with risk in this unscreened Romanian population.