Allele Frequencies Of Single Nucleotide Polymorphisms Research Articles

Association of drug-related polymorphisms with palbociclib-related neutropenia: Pharmacogenetic analysis of PALOMA-2/-3 (P2/3).

1060 Background: The most common PAL treatment related adverse event is neutropenia. ABCB1 and ERCC1 variants are associated with increased chemotherapy drug exposure and CYP3A7*1C may be associated with reduced exposure. Pharmacogenetic analyses of these variants in patients (pts) from P2/3 may reveal associations between single nucleotide polymorphisms (SNPs) and early occurrence of grade 3/4 (G3/4) neutropenia. Methods: ABCB1 (rs1045642, rs1128503), ERCC1 (rs3212986, rs11615), and CYP3A7*1C (rs45446698) variants were analyzed in germline DNA from pts with HR+/HER2– advanced breast cancer from P2 (n=584) and P3 (n=442) by TaqMan assay. Association between variants and incidence of G3/4 low absolute neutrophil count (ANC) at Cycle 1 Day 15 (C1D15) was assessed with the exact Cochran-Armitage trend test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. Results: In total, 652 PAL-treated pts had SNP, race, and C1D15 ANC data. Minor allele frequencies (MAF), incidence rates, and relative risk of G3/4 C1D15 ANC for ABCB1 and ERCC1 variants are given in the Table. CYP3A7*1C was only found in non-Asians (MAF 6%). Conclusions: This is the first comprehensive assessment of pharmacogenetic data from P2/3. ABCB1 and ERCC1 SNP allele frequencies differ between Asians and non-Asians. Despite combining P2/3 data, we lacked power to detect moderate associations; further investigation of these SNPs with G3/4 C1D15 ANC is warranted. Pfizer Clinical trial information: NCT01740427, NCT01942135. [Table: see text]

Establishing a second-tier panel of 18 ancestry informative markers to improve ancestry distinctions among Asian populations

At present, several mature ancestry informative SNP (AISNP) panels are used to distinguish between continental regions of the world, but a more accurate division within the continent requires a secondary panel to complete. However, many AISNPs for the subgroup ancestry inference are selected from the Kidd Lab panel of 55 AISNPs or other published papers. These panels inevitably lack valuable markers for subgroup ancestry inference. Therefore, instead of choosing from the published panels, we used the 1000 Genomes Project to screen potentially informational markers in Asian populations, including single nucleotide polymorphisms (SNPs) and insertion/deletion polymorphisms (InDels). The allele frequencies of all autosomal SNPs and InDels of the 1000 Genomes Project were compared between 10 populations in Asia to identify markers with the largest pairwise allele frequency differences. Finally, we established a second-tier panel of 18 AIMs in this study, which not only divided the 26 populations of the 1000 Genomes Project into six clusters, but also divided the Asia subgroup into four clusters: Gujarati, East Asia, Southeast Asia and South Asia.

Molecular expression and single nucleotide polymorphisms of the IL17A gene among etanercept-treated rheumatoid arthritis patients

Molecular expression (reverse transcription-quantitative polymerase chain reaction; RT-qPCR) and DNA-sequencing-based single nucleotide polymorphisms (SNPs) of interleukin 17A (IL17A) gene were determined in 51 etanercept-treated Iraqi rheumatoid arthritis (RA) patients and 45 control. The results revealed that the relative expression (2-∆∆Ct) of the IL17A gene was increased by 1.28 ± 0.29 fold in RA patients, and such profile was approximated in males (1.66 ± 0.58) and female (1.01 ± 0.28) patients. Concerning PCR-amplified DNA sequences, out of the 10 encountered SNPs, two SNPs (rs8193038 and rs3819025) showed allele frequencies that exceeded 10%. The rs8193038 SNP allele and genotype frequencies showed no significant variations between RA patients and control. The second SNP (rs3819025) was observed to have three genotypes (AA, AG, and GG). Among these genotypes, it was observed that the homozygous genotype of the mutant allele (GG) was only recorded in patients with a frequency of 13.7%, while none of the control had this genotype. Such a difference was significant even after the correction of probability (pc = 0.05), and the associated OR was 15.34 (95% C.I.: 1.39 - 169.24). It was also observed that G allele showed a significant increased frequency in patients (25.5 vs. 12.2%; OR = 2.46; 95% C.I.: 1.14 - 5.30; p = 0.015), while A allele frequency was significantly decreased (74.5 vs. 87.8%; OR = 0.41; 95% C.I.: 0.19 - 0.88; p = 0.015). However, the significance in both cases was lost when the probability was corrected. It was also observed that there was no significant impact of the rs3819025 SNP genotypes on the expression of the IL17A gene. In conclusion, the IL17A gene showed an increased expression in RA patients, and rs3024419 SNP is suggested to be associated with an increased risk to develop the disease in the Iraqi population.

Population Levels Assessment of the Distribution of Disease-Associated Variants With Emphasis on Armenians - A Machine Learning Approach.

Background: During the last decades a number of genome-wide association studies (GWASs) has identified numerous single nucleotide polymorphisms (SNPs) associated with different complex diseases. However, associations reported in one population are often conflicting and did not replicate when studied in other populations. One of the reasons could be that most GWAS employ a case-control design in one or a limited number of populations, but little attention was paid to the global distribution of disease-associated alleles across different populations. Moreover, the majority of GWAS have been performed on selected European, African, and Chinese populations and the considerable number of populations remains understudied.Aim: We have investigated the global distribution of so far discovered disease-associated SNPs across worldwide populations of different ancestry and geographical regions with a special focus on the understudied population of Armenians.Data and Methods: We have used genotyping data from the Human Genome Diversity Project and of Armenian population and combined them with disease-associated SNP data taken from public repositories leading to a final dataset of 44,234 markers. Their frequency distribution across 1039 individuals from 53 populations was analyzed using self-organizing maps (SOM) machine learning. Our SOM portrayal approach reduces data dimensionality, clusters SNPs with similar frequency profiles and provides two-dimensional data images which enable visual evaluation of disease-associated SNPs landscapes among human populations.Results: We find that populations from Africa, Oceania, and America show specific patterns of minor allele frequencies of disease-associated SNPs, while populations from Europe, Middle East, Central South Asia, and Armenia mostly share similar patterns. Importantly, different sets of SNPs associated with common polygenic diseases, such as cancer, diabetes, neurodegeneration in populations from different geographic regions. Armenians are characterized by a set of SNPs that are distinct from other populations from the neighboring geographical regions.Conclusion: Genetic associations of diseases considerably vary across populations which necessitates health-related genotyping efforts especially for so far understudied populations. SOM portrayal represents novel promising methods in population genetic research with special strength in visualization-based comparison of SNP data.

Screening of underlying genetic biomarkers for ankylosing spondylitis.

Genetic biomarkers for the diagnosis of ankylosing spondylitis (AS) remain unreported except for human leukocyte antigen B27 (HLA-B27). Therefore, the aim of the present study was to screen the differentially expressed genes (DEGs), and those that also possess differential single nucleotide polymorphism (SNP) loci in the whole blood of AS patients compared with healthy controls by integrating two mRNA expression profiles (GSE73754 and GSE25101) and SNP microarray data (GSE39428) collected from the Gene Expression Omnibus (GEO). Using the t-test, 1,056 and 1,073 DEGs were identified in the GSE73754 and GSE25101 datasets, respectively. Among them, 234 DEGs were found to be shared in both datasets, which were subsequently overlapped with 122 differential SNPs of genes in the GSE39428 dataset, resulting in identification of two common genes [eukaryotic translation elongation factor 1 epsilon 1 (EEF1E1) and serpin family A member 1 (SERPINA1)]. Their expression levels were significantly upregulated and the average expression log R ratios of SNP sites in these genes were significantly higher in AS patients than those in controls. Function enrichment analysis revealed that EEF1E1 was involved in AS by influencing the aminoacyl-tRNA biosynthesis, while SERPINA1 may be associated with AS by participating in platelet degranulation. However, only the genotype and allele frequencies of SNPs (rs7763907 and rs7751386) in EEF1E1 between AS and controls were significantly different between AS and the controls, but not SERPINA1. These findings suggest that EEF1E1 may be an underlying genetic biomarker for the diagnosis of AS.

Coalescent models characterize sources and demographic history of recent round goby colonization of Great Lakes and inland waters.

The establishment and spread of aquatic invasive species are ecologically and economically harmful and a source of conservation concern internationally. Processes of species invasion have traditionally been inferred from observational data of species presence/absence and relative abundance. However, genetic‐based approaches can provide valuable sources of inference. Restriction site‐associated DNA sequencing was used to identify and genotype single nucleotide polymorphism (SNP) loci for Round Gobies (Neogobius melanostomus) (N = 440) from 18 sampling locations in the Great Lakes and in three Michigan, USA, drainages (Flint, Au Sable, and Cheboygan River basins). Sampled rivers differed in size, accessibility, and physical characteristics including man‐made dispersal barriers. Population levels of genetic diversity and interpopulation variance in SNP allele frequency were used in coalescence‐based approximate Bayesian computation (ABC) to statistically compare models representing competing hypotheses regarding source population, postcolonization dispersal, and demographic history in the Great Lakes and inland waters. Results indicate different patterns of colonization across the three drainages. In the Flint River, models indicate a strong population bottleneck (<3% of contemporary effective population size) and a single founding event from Saginaw Bay led to the colonization of inland river segments. In the Au Sable River, analyses could not distinguish potential source populations, but supported models indicated multiple introductions from one source population. In the Cheboygan River, supported models indicated that colonization likely proceeded from east (Lake Huron source) to west among inland locales sampled in the system. Despite the recent occupancy of Great Lakes and inland habitats, large numbers of loci analyzed in an ABC framework enable statistically supported identification of source populations and reconstruction of the direction of inland spread and demographic history following establishment. Information from analyses can direct management actions to limit the spread of invasive species from identified sources and most probable vectors into additional inland aquatic habitats.

Association of rs10490924 in ARMS2/HTRA1 with age-related macular degeneration in the Pakistani population.

Age-related macular degeneration (AMD) is a disease of the elderly in which central vision is lost because of degenerative changes of the macula. The current study investigated the association of single-nucleotide polymorphisms (SNPs) with AMD in the Pakistani population. Four SNPs were analyzed in this study: rs1061170 in the CFH, rs429608 near CFB, rs2230199 in the C3, and rs10490924 in ARMS2/HTRA1. This case-control association study was conducted on 300 AMD patients (125 wet AMD and 175 dry AMD) and 200 unaffected age- and gender-matched control individuals. The association of the SNP genotypes and allele frequency distributions were compared between patients and healthy controls, keeping age, gender, and smoking status as covariates. A significant genotype and variant allele association was found of rs10490924 in ARMS2/HTRA1 with wet AMD, while the SNPs in CFH, CFB, and C3 were not associated with AMD in the current Pakistani cohort. The lack of association of CFH, CFB, and C3 may be attributed to limited sample size. This study demonstrates that genetic causative factors of AMD differ among populations and supports the need for genetic association studies among cohorts from various populations to increase our global understanding of the disease pathogenesis.

Genomic Dissection of Nonhost Resistance to Wheat Stem Rust in Brachypodium distachyon.

The emergence of new races of Puccinia graminis f. sp. tritici, the causal pathogen of wheat stem rust, has spurred interest in developing durable resistance to this disease in wheat. Nonhost resistance holds promise to help control this and other diseases because it is durable against nonadapted pathogens. However, the genetic and molecular basis of nonhost resistance to wheat stem rust is poorly understood. In this study, the model grass Brachypodium distachyon, a nonhost of P. graminis f. sp. tritici, was used to genetically dissect nonhost resistance to wheat stem rust. A recombinant inbred line (RIL) population segregating for response to wheat stem rust was evaluated for resistance. Evaluation of genome-wide cumulative single nucleotide polymorphism allele frequency differences between contrasting pools of resistant and susceptible RILs followed by molecular marker analysis identified six quantitative trait loci (QTL) that cumulatively explained 72.5% of the variation in stem rust resistance. Two of the QTLs explained 31.7% of the variation, and their interaction explained another 4.6%. Thus, nonhost resistance to wheat stem rust in B. distachyon is genetically complex, with both major and minor QTLs acting additively and, in some cases, interacting. These findings will guide future research to identify genes essential to nonhost resistance to wheat stem rust.

GRM7 polymorphisms and risk of schizophrenia in Iranian population.

The role of metabotropic glutamate receptors in the pathogenesis of schizophrenia or response to antipsychotic treatment has been proposed previously. The aim of the current study was to investigate the associations between two intronic variants within GRM7 gene (rs6782011 and rs779867) and schizophrenia in Iranian population. These two single nucleotide polymorphisms (SNPs) were genotyped in 273 schizophrenic patients and 300 age and sex-matched normal controls. The frequency of A allele of the rs779867 was significantly lower in the schizophrenic patients compared with healthy subjects (OR (95% CI) = 0.71 (0.56-0.89), adjusted P value = 0.008). This SNP was associated with schizophrenia in co-dominant and dominant models (adjusted P values of 0.03 and 0.02 respectively). However, there was no difference in allele and genotype frequencies of the rs6782011 SNP between cases and controls. Consequently, the results of current study further highlight the participation of GRM7 in the pathogenesis of schizophrenia.

Interleukin-1 single nucleotide polymorphisms as risk factors for susceptibility of inflammatory bowel disease: an Iraqi Arab population-based study

ABSTRACTObjectives: It is aimed to determine the association between four single-nucleotide polymorphisms (SNPs) of IL1 genes (rs1800587: IL1A−889 C/T, rs16944: IL1B−511 T/C, rs2234650: IL1R1pst1 1970 T/C and rs315952: IL1RAmspa1 11100 T/C) and the two types of IBD (UC and CD) in samples of Iraqi Arab patients.Materials and Methods: Hundred Iraqi patients (66 UC and 34 CD) were genotyped for these SNPs by polymerase chain reaction-specific sequence primer (PCR-SSP) assay.Results: A significant increased frequency of IL1A−889 C allele was observed in total IBD patients compared to controls (72.0 vs. 56.5%; Odds ratio = 1.98; Corrected p = 0.001). For IL1B−511 and IL1R1pstl 1970 SNPs, the T allele frequency was significantly increased in total patients (62.0 vs. 49.1%; Odds ratio = 1.69; Corrected p = 0.02 and 65.0 vs. 46.7%; Odds ratio = 2.12; Corrected p = 1 × 10−4, respectively). Allele and genotype frequencies of IL1RAmspa 11100 SNP showed no significant variation between total patients and controls. A similar profile of was observed in UC patients, but IL1RAmspa 11100 T allele frequency was significantly increased in patients (72.7 vs. 60.2%; Odds ratio = 1.76; Corrected p = 0.05). Among CD patients, IL1A−889, IL1R1pstl 1970 and IL1RAmspa 11100 SNP allele frequencies shared their distribution in total IBD patients. For IL1B−511 SNP, allele and genotype frequencies showed no significant difference between CD patients and controls.Conclusion: These data suggests a significant role of IL1 SNPs in etiopathogenesis of IBD in Iraqi Arab population.

Bone Morphogenetic Protein 6 Polymorphisms are Associated With Systemic Lupus Erythematosus Susceptibility in the Korean Population.

This study aims to investigate whether bone morphogenetic protein 6 (BMP6) single-nucleotide polymorphism (SNP) is associated with susceptibility to systematic lupus erythematosus (SLE). We analyzed the genotype and allele frequencies of BMP6 SNPs using genomic deoxyribonucleic acid isolated from 119 SLE patients (9 males, 110 females; mean age 36.4 years; range 19 to 59 years) and 509 healthy controls (323 males, 186 females; mean age 42.1 years; range 19 to 61 years). Genomic deoxyribonucleic acid was extracted from peripheral blood leukocytes using a standard phenol-chloroform method or by using a genomic deoxyribonucleic acid extraction kit. Erythrocyte sedimentation rate, C-reactive protein, and antinuclear antibody levels of SLE patients were recorded. Our results showed that the genotype frequencies of rs17557 and rs9505273 for BMP6 in SLE patients significantly differed from those of the control group (p=0.01 and p=0.04, respectively). The genotype frequencies of the rs17557 and rs9505273 for BMP6 in female SLE patients were also significantly different from those in female healthy controls (p=0.04 and p=0.03, respectively). We also revealed that the distribution of the main haplotypes of BMP6 SNPs in SLE patients was significantly different from their distribution in healthy controls. These results suggested that SNPs in BMP6 might be associated with susceptibility to SLE and that haplotypes of BMP6 polymorphisms might represent useful genetic markers for SLE.

Association of uncoupling protein gene polymorphisms with essential hypertension in a northeastern Han Chinese population.

Uncoupling proteins (UCPs) belong to the family of mitochondrial transporter proteins and mediate regulated proton leak across the inner mitochondrial membrane. The UCPs play an important role in energy homeostasis and reactive oxygen species (ROS) release, and have been established as candidate genes for obesity, diabetes and hypertension. This study examined the possible association between the single nucleotide polymorphisms (SNPs) of UCP1-3 genes and essential hypertension (EH) in a northeastern Han Chinese population. A total of 2207 Chinese Han subjects were enrolled, including 1045 normotensives and 1162 hypertensives. Genotyping of UCP1 rs1800592, UCP1 rs12502572, UCP2 rs659366, UCP2 rs660339, and UCP3 rs3781907 was detected using Sequenom MassArray System. SHEsis was used to analyze linkage disequilibrium and haplotype. No evident association was observed between the genotype distributions and allele frequencies of individual SNPs and EH. Haplotype analysis showed the haplotype GAATA (rs1800592-rs12502572-rs659366-rs660339-rs3781907) was significantly associated with lower EH risk (p = 0.001, χ2 = 10.861, OR = 0.634, 95% CI = 0.483-0.833), and AGATG was associated with increased EH risk (p = 0.012, χ2 = 6.287, OR = 1.265, 95% CI = 1.052-1.521). These findings suggest haplotypes of UCP1-3 genes are linked to EH risk in a northeastern Han Chinese population. Further investigation with larger sample size in multiethnic population is needed to confirm our results.

TargetClone: A multi-sample approach for reconstructing subclonal evolution of tumors.

Most tumors are composed of a heterogeneous population of subclones. A more detailed insight into the subclonal evolution of these tumors can be helpful to study progression and treatment response. Problematically, tumor samples are typically very heterogeneous, making deconvolving individual tumor subclones a major challenge. To overcome this limitation, reducing heterogeneity, such as by means of microdissections, coupled with targeted sequencing, is a viable approach. However, computational methods that enable reconstruction of the evolutionary relationships require unbiased read depth measurements, which are commonly challenging to obtain in this setting. We introduce TargetClone, a novel method to reconstruct the subclonal evolution tree of tumors from single-nucleotide polymorphism allele frequency and somatic single-nucleotide variant measurements. Furthermore, our method infers copy numbers, alleles and the fraction of the tumor component in each sample. TargetClone was specifically designed for targeted sequencing data obtained from microdissected samples. We demonstrate that our method obtains low error rates on simulated data. Additionally, we show that our method is able to reconstruct expected trees in a testicular germ cell cancer and ovarian cancer dataset. The TargetClone package including tree visualization is written in Python and is publicly available at https://github.com/UMCUGenetics/targetclone.

Determining association of rho kinase 1 gene polymorphisms with risk of Alzheimer's disease: a multicenter pilot study.

In addition to the increasing evidence for a molecular mechanism of rho kinase 1 (ROCK1) in Alzheimer's disease (AD), there are several published studies regarding the relationship between ROCK1 gene polymorphisms and neurological diseases. However, it is unknown whether there is an association between the polymorphisms of ROCK1 and AD. We sought to identify the potential association between ROCK1 gene polymorphisms and AD in the Chinese Han population. A total of 295 patients with AD and 206 healthy controls from multiple centers were enrolled in this study. Three single-nucleotide polymorphisms (SNPs) (rs35996865, rs11873284, and rs2127958) in ROCK1 gene were analyzed using Sanger sequencing. We did not find any significant differences between AD and control groups with regards to the frequency of these three ROCK1 polymorphisms. Further, the three SNP genotype frequencies and allele frequencies did not show significant differences between patients of AD and controls in APOE4-stratified subjects (P>0.01). Additionally, the three SNPs did not show significant differences even when adopting a four-inheritance model by logistic regression. This is the first multicenter pilot study to evaluate the contribution of ROCK1 genetic variance to AD risk. Our data demonstrated that the ROCK1 gene may not influence the risk of AD by interacting with APOE among Chinese Han people.

A3440 rs1275988 and rs2586886 in TASK-1 gene may be a protective genetic markers of Obstructive Sleep Apnea in obese patients

Objectives: Acid-sensitive K+ channels (TASK-1) are sensitive to changes in extracellular pH in the physiological range, which have been implicated in peripheral and central respiratory chemosensitivity. We sought to assess the association between the human TASK-1 genetic polymophisms and obstructive sleep apnea (OSA). Methods: 154 severe OSA patients and 156 non-OSA individuals were collected baseline characteristics and genotyped for rs1275988 and rs2586886 single nucleotide polymorphisms (SNPs) of the human TASK-1 gene by a Kompetitive Allele Specific PCR genotyping system. The association between genotypes and OSA status was assessed. Results: No significant differences in the genotype distribution and allele frequencies of SNPs (rs1275988 and rs2586886) were found between severe OSA patients and non-OSA groups. Stratified by BMI, the distribution of SNPs (rs1275988 and rs2586886) genotype distribution, allele frequencies, recessive model (GG+GA vs AA) and dominant model (GG vs AA + GA) showed a significant difference between severe OSA groups and non-OSA groups in patients with BMI≥28 kg/m2 (for genotype: P = 0.034 and P = 0.025, respectively; for allele: P = 0.007 and P = 0.002, respectively; for Recessive model: P = 0.027 and P = 0.013, respectively; for dominant model: P = 0.038 and P = 0.046, respectively). The multivariate logistic regression analysis showed that the AA genotype was a protective factor for OSA[for rs1275988:OR = 0.340 (95% CI: 0.120–0.966; for rs2586886: OR = 0.283 (95%CI:0.097–0.832) respectively]. Conclusion: The rs1275988 and rs2586886 SNPs in TASK-1 may be a protective genetic markers to OSA in obese patients.

IL1R1 and IL1R2 polymorphisms were associated with tuberculosis risk: A pilot study.

Interleukin (IL)-1 has been reported to be involved in the development of tuberculosis (TB). IL1R1 and IL1R2 encode a cytokine receptor that belongs to the IL-1 receptor family. However, few studies have reported on the polymorphisms of IL1R1 and IL1R2 in TB patients. We investigated nine single-nucleotide polymorphisms (SNPs) in IL1R1 and IL1R2 in 300TB patients and 300 controls, aiming to evaluate their association with TB risk. Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression after adjusting for age and gender. On comparing the allele frequencies of candidate SNPs, we found that the minor allele 'A' of rs4851527 in IL1R2 was associated with a decreased risk of TB, whereas the minor alleles of rs10490571, rs956730 and rs3917225 in IL1R1 were associated with an increased risk of TB (p<0.05). In the genetic model analysis, we found that the allele 'A' of rs4851527 was correlated with a decreased risk of TB in a log-additive model, whereas the minor alleles of rs719250, rs3218977, rs10490571, rs956730 and rs3917225 were correlated with an increased risk of TB in dominant and log-additive models (p<0.05). Additionally, we found three haplotypes that were associated with an increased risk of TB: TGCT and TGTT haplotypes constructed by rs11674595, rs4851527, rs719250 and rs3218896, as well as GA haplotype constructed by rs3218977 and rs2072472 (p<0.05). Our data shed new light on the association between genetic polymorphisms of IL1R1 and IL1R2 and TB susceptibility in the Chinese Han population.

A novel SNP-set analytical method without distinguishing common variants or rare variants in genome-wide association study

Single nucleotide polymorphism (SNP)-set analysis in genome-wide association studies (GWASs) has become a hot topic. Most existing SNP-set analystic methods are designed and work well according to the different natures of common or rare variants and associated diseases. But the information that the disease associated variants are common or rare cannot be gained in advance. Therefore, in this research, we proposed a new and powerful weighted function method without distinguishing common or rare variants to select tagging SNP-set. We applied our selection method to sequence kernel association test (SKAT) and compared the power with some existing methods. The simulation results showed that our method has higher power not only than SKAT in un-weighted case, but also than SKAT in other weighted functions. Moreover, the power is improved significantly when the minor allele frequency (MAF) of causal SNP is relatively small.

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype.

ObjectiveThe basis for clinical variation related to underlying progressive supranuclear palsy (PSP) pathology is unknown. We performed a genome‐wide association study (GWAS) to identify genetic determinants of PSP phenotype.MethodsTwo independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson syndrome (RS) and non‐RS groups. We carried out separate logistic regression GWASs to compare RS and non‐RS groups and then combined datasets to carry out a whole cohort analysis (RS = 367, non‐RS = 130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/coexpression patterns of our identified genes and used our data to carry out gene‐based association testing.ResultsOur lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome‐wide significance in our whole cohort analysis (odds ratio = 5.5, 95% confidence interval = 3.2–10.0, p = 1.7 × 10−9). rs564309 is an intronic variant of the tripartite motif‐containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene‐based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia.InterpretationOur study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease‐modifying therapies. Ann Neurol 2018;84:485–496

Interleukin (IL)-8 polymorphisms contribute in suicide behavior

Previous studies have highlighted the role of immune dysregulation in suicide behavior. Interleukin (IL)-8 is a chemokine with neuroprotective effects whose lower serum concentrations have been detected in individuals committed suicide. In the present study, we genotyped three single nucleotide polymorphisms (SNPs) within IL-8 gene (rs4073, rs2227306 and rs1126647) in 229 individuals who attempted suicide with soft suicide methods, 235 suicide victims and 290 individuals without any history of psychiatric disorders or suicide attempt. The T allele of rs4073 was significantly over-represented in suicide attempt group compared with both control and completed suicide groups (adjusted P values of 8.3E-7 and 9.8E-8 respectively). This SNP was associated with suicide attempt in both dominant and co-dominant models (P values of 6.2E−9 and 4.3 E−8 respectively). The genotype and allele frequencies of other SNPs were not significantly different among the three study groups. The T C A haplotype (rs4073, rs2227306 and rs1126647 respectively) were significantly less prevalent in completed suicide group compared with suicide attempt group (OR (95% CI) = 0.63 (0.46–0.86), adjusted P value = 0.03). Besides, the A T A haplotype has significant lower frequency in individuals who attempted soft suicide compared with controls (OR (95% CI) = 0.44 (0.26–0.75), adjusted P value = 0.02). However, this haplotype was significantly more prevalent in individuals attempted hard methods compared with those attempted soft methods (OR (95% CI) = 2.21 (1.26–3.87), adjusted P value = 0.04). The present study provided further evidence for the role of IL-8 in suicide behavior.

The feasibility of using low-density marker panels for genotype imputation and genomic prediction of crossbred dairy cattle of East Africa

Cost-effective high-density (HD) genotypes of livestock species can be obtained by genotyping a proportion of the population using a HD panel and the remainder using a cheaper low-density panel, and then imputing the missing genotypes that are not directly assayed in the low-density panel. The efficacy of genotype imputation can largely be affected by the structure and history of the specific target population and it should be checked before incorporating imputation in routine genotyping practices. Here, we investigated the efficacy of imputation in crossbred dairy cattle populations of East Africa using 4 different commercial single nucleotide polymorphisms (SNP) panels, 3 reference populations, and 3 imputation algorithms. We found that Minimac and a reference population, which included a mixture of crossbred and ancestral purebred animals, provided the highest imputation accuracy compared with other scenarios of imputation. The accuracies of imputation, measured as the correlation between real and imputed genotypes averaged across SNP, were around 0.76 and 0.94 for 7K and 40K SNP, respectively, when imputed up to a 770K panel. We also presented a method to maximize the imputation accuracy of low-density panels, which relies on the pairwise (co)variances between SNP and the minor allele frequency of SNP. The performance of the developed method was tested in a 5-fold cross-validation process where various densities of SNP were selected using the (co)variance method and also by alternative SNP selection methods and then imputed up to the HD panel. The (co)variance method provided the highest imputation accuracies at almost all marker densities, with accuracies being up to 0.19 higher than the random selection of SNP. The accuracies of imputation from 7K and 40K panels selected using the (co)variance method were around 0.80 and 0.94, respectively. The presented method also achieved higher accuracy of genomic prediction at lower densities of selected SNP. The squared correlation between genomic breeding values estimated using imputed genotypes and those from the real 770K HD panel was 0.95 when the accuracy of imputation was 0.64. The presented method for SNP selection is straightforward in its application and can ensure high accuracies in genotype imputation of crossbred dairy populations in East Africa.