Infection due to 2009 pandemic H1N1 influenza A virus (A[H1N1]pdm09) is commonly manifested as mild infection but occasionally as severe pneumonia. We hypothesized that host genetic variations may contribute to disease severity. An initially small-scale genome-wide association study guided the selection of CD55 single-nucleotide polymorphisms in 425 Chinese patients with severe (n = 177) or mild (n = 248) disease. Carriers of rs2564978 genotype T/T were significantly associated with severe infection (odds ratio, 1.75; P = .011) under a recessive model, after adjustment for clinical confounders. An allele-specific effect on CD55 expression was revealed and ascribed to a promoter indel variation, which was in complete linkage disequilibrium with rs2564978. The promoter variant with deletion exhibited significantly lower transcriptional activity. We further demonstrated that CD55 can protect respiratory epithelial cells from complement attack. Additionally, A(H1N1)pdm09 infection promoted CD55 expression. In conclusion, CD55 polymorphisms are associated with severe A(H1N1)pdm09 infection. CD55 may exert a substantial impact on the disease severity of A(H1N1)pdm09 infection.

Adolescent idiopathic scoliosis (AIS) is the most common musculoskeletal disorder of childhood development. The genetic architecture of AIS is complex, and the great majority of risk factors are undiscovered. To identify new AIS susceptibility loci, we conducted the first genome-wide meta-analysis of AIS genome-wide association studies, including 7956 cases and 88 459 controls from 3 ancestral groups. Three novel loci that surpassed genome-wide significance were uncovered in intragenic regions of the CDH13 (P-value rs4513093 = 1.7E-15), ABO (P-value rs687621 = 7.3E-10) and SOX6 (P-value rs1455114 = 2.98E-08) genes. Restricting the analysis to females improved the associations at multiple loci, most notably with variants within CDH13 despite the reduction in sample size. Genome-wide gene-functional enrichment analysis identified significant perturbation of pathways involving cartilage and connective tissue development. Expression of both SOX6 and CDH13 was detected in cartilage chondrocytes and chromatin immunoprecipitation sequencing experiments in that tissue revealed multiple HeK27ac-positive peaks overlapping associated loci. Our results further define the genetic architecture of AIS and highlight the importance of vertebral cartilage development in its pathogenesis.

Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.

In this case-controlled study, we tested susceptible genetic variants for Alzheimer's disease (AD) in CR1, CLU and PICALM from genome-wide association studies (GWAS) in a southern Chinese population. Eight hundred twelve participants consisting of 462 late-onset Alzheimer's disease (LOAD) patients and 350 nondemented control subjects were recruited. We found by multivariate logistic regression analysis, that single nucleotide polymorphisms (SNPs) in CR1 (rs6656401 adjusted allelic p = 0.035; adjusted genotypic p = 0.043) and CLU (rs2279590 adjusted allelic p = 0.035; adjusted genotypic p = 0.006; rs11136000 adjusted allelic p = 0.038; adjusted genotypic p = 0.009) were significantly different between LOAD patients and nondemented controls. For PICALM, LOAD association was found only in the APOE ε4 (-) subgroup (rs3851179 adjusted allelic p = 0.028; adjusted genotypic p = 0.013). Our findings showed evidence of CR1, CLU, and PICALM and LOAD susceptibility in an independent southern Chinese population, which provides additional evidence for LOAD association apart from prior genome-wide association studies in Caucasian populations.

A study was conducted to validate the most significant single nucleotide polymorphism (SNP) from a genome-wide association study of Japanese adolescent idiopathic scoliosis (AIS) patients in an independent southern Chinese population. In total, 300 AIS patients fulfilled the clinical criteria and 788 controls with MRI scans of the spine were included in the replication study. We employed case-control analysis to study the association of SNP rs11190870 near LBX1 (ladybird homeobox 1) with AIS in a southern Chinese population. The results suggest that SNP rs11190870 is significantly associated with AIS (P¼9.1Â10 À10 ; odds ratio¼1.85; 95% confidence interval¼1.52-2.25). The results of this study confirm that SNP rs11190870 is associated with AIS. Keywords: adolescent idiopathic scoliosis; replication study; rs11190870; southern Chinese INTRODUCTIONThe most common form of scoliosis is adolescent idiopathic scoliosis (AIS). AIS affects 1-4% of children aged between 10 and 16 years, 1,2 and affects more females than males. 3,4 It is known that the inheritance of AIS is complex. The role of genetic factors in scoliosis is well-documented and widely accepted. 5-8 Genome-wide linkage analyses have identified susceptibility loci on chromosome 6p, 8q12, 9q31.2-q34. 2, 10q, 12p, 17p11, 17q25.30-qtel, 18q, 19p13 and chromosome X. 9-16 Several candidate gene studies have also reported that genes such as COL1A1, COL1A2, FBN1, ESR, MATN1, MTNR1B, CHD7, VDR and GPER were associated with scoliosis. 10,[17][18][19][20][21][22][23][24] Recently, a genome-wide association study (GWAS) has been applied to identify the susceptibility loci of AIS. 25 The single nucleotide polymorphism (SNP) rs11190870 that is located in the 3¢-flanking region of LBX1 (ladybird homeobox 1) gene at chromosome 10q24.31 was identified as the most significant common variant in Japanese females with P¼1.24Â10 19 ; odds ratio (OR)¼1.56. 25 In the present study, we conducted a study to validate the association of rs11190870 with AIS in an independent southern Chinese population that contains 300 cases and 788 controls. Our results suggest that the SNP rs11190870 is highly significantly associated with AIS. MATERIALS AND METHODS SubjectsInformed consent was obtained from all individuals participating in this study. A cohort consisting of 300 AIS patients was recruited at the Duchess of Kent Children's Hospital in Hong Kong. The patient selection criteria for the study are as follows: (1) Patients with idiopathic scoliosis deformity involving the thoracic plus or minus the lumbar spine with Cobb's angles more than 35 degrees and required surgical operations in Duchess of Kent Children's Hospital. (2) The onset of scoliosis deformity was after 10 years and under 20 years of age. (3) Neuromuscular, congenital and syndromal scoliosis individuals were excluded by history taking, physical examination and X-ray of the spine. The control samples were from a large data set of southern Chinese population (3500 samples) recruited for a study on the genetics of degenera...

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the misannotation of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS that may result due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model including mostly one rare variant deletion CNV allele and one common variant noncoding hypomorphic haplotype of the TBX6 gene. We demonstrate that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study that can be ‘induced’ by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p<1×10−6 and p=0.034, respectively), indicating that such locus co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We propose that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits may improve genetic model analyses and better integrate. GWAS with robust Mendelian principles

BackgroundRecently, several tools have been designed for human leukocyte antigen (HLA) typing using single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) data. These tools provide high-throughput and cost-effective approaches for identifying HLA types. Therefore, tools for downstream association analysis are highly desirable. Although several tools have been designed for multi-allelic marker association analysis, they were designed only for microsatellite markers and do not scale well with increasing data volumes, or they were designed for large-scale data but provided a limited number of tests.ResultsWe have developed a Python package called PyHLA, which implements several methods for HLA association analysis, to fill the gap. PyHLA is a tailor-made, easy to use, and flexible tool designed specifically for the association analysis of the HLA types imputed from genome-wide genotyping and NGS data. PyHLA provides functions for association analysis, zygosity tests, and interaction tests between HLA alleles and diseases. Monte Carlo permutation and several methods for multiple testing corrections have also been implemented.ConclusionsPyHLA provides a convenient and powerful tool for HLA analysis. Existing methods have been integrated and desired methods have been added in PyHLA. Furthermore, PyHLA is applicable to small and large sample sizes and can finish the analysis in a timely manner on a personal computer with different platforms. PyHLA is implemented in Python. PyHLA is a free, open source software distributed under the GPLv2 license. The source code, tutorial, and examples are available at https://github.com/felixfan/PyHLA.

Circular RNA (circRNA) is a new class of non-coding RNA that has recently attracted researchers' interest. Studies have demonstrated that circRNA can function as microRNA sponges or competing endogenous RNAs. Although circRNA has been explored in some species and tissues, the genetic basis of testis development and spermatogenesis in cattle remains unknown. We performed ribo-depleted total RNA-Seq to detect circRNA expression profiles of neonatal (one week old) and adult (4 years old) Qinchuan cattle testes. We obtained 91 112 596 and 80 485 868 clean reads and detected 21 753 circRNAs. A total of 4248 circRNAs were significantly differentially expressed between neonatal and adult cattle testes. Among these circRNAs, 2225 were upregulated, and 2023 were downregulated in adult cattle testis. Genomic feature, length distribution and other characteristics of the circRNAs in cattle testis were studied. Moreover, Gene Ontology and KEGG pathway analyses were performed for source genes of circRNAs. These source genes were mainly involved in tight junction, adherens junction, TGFβ signalling pathway and reproduction, such as PIWIL1, DPY19L2, SLC26A8, IFT81, SMC1B, IQCG and TTLL5. CircRNA expression patterns were validated by RT-qPCR. Our discoveries provide a solid foundation for the identification and characterization of key circRNAs involved in testis development or spermatogenesis.