Efficient estimation for large-scale linkage disequilibrium patterns of the human genome.

In this study, we proposed an efficient algorithm (X-LD) for estimating linkage disequilibrium (LD) patterns for a genomic grid, which can be of inter-chromosomal scale or of small segments. Compared with conventional methods, the proposed method was significantly faster, dropped from O(nm2) to O(n2m)-n the sample size and m the number of SNPs, and consequently we were permitted to explore in depth unknown or reveal long-anticipated LD features of the human genome. Having applied the algorithm for 1000 Genome Project (1KG), we found (1) the extended LD, driven by population structure, universally existed, and the strength of inter-chromosomal LD was about 10% of their respective intra-chromosomal LD in relatively homogeneous cohorts, such as FIN, and to nearly 56% in admixed cohort, such as ASW. (2) After splitting each chromosome into upmost of more than a half million grids, we elucidated the LD of the HLA region was nearly 42 folders higher than chromosome 6 in CEU and 11.58 in ASW; on chromosome 11, we observed that the LD of its centromere was nearly 94.05 folders higher than chromosome 11 in YRI and 42.73 in ASW. (3) We uncovered the long-anticipated inversely proportional linear relationship between the length of a chromosome and the strength of chromosomal LD, and their Pearson's correlation was on average over 0.80 for 26 1KG cohorts. However, this linear norm was so far perturbed by chromosome 11 given its more completely sequenced centromere region. Uniquely chromosome 8 of ASW was found most deviated from the linear norm than any other autosomes. The proposed algorithm has been realized in C++ (called X-LD) and is available at https://github.com/gc5k/gear2, and can be applied to explore LD features in any sequenced populations.

Subsampling Technique to Estimate Variance Component for UK-Biobank Traits.

The estimation of heritability has been an important question in statistical genetics. Due to the clear mathematical properties, the modified Haseman-Elston regression has been found a bridge that connects and develops various parallel heritability estimation methods. With the increasing sample size, estimating heritability for biobank-scale data poses a challenge for statistical computation, in particular that the calculation of the genetic relationship matrix is a huge challenge in statistical computation. Using the Haseman-Elston framework, in this study we explicitly analyzed the mathematical structure of the key term tr( K T K ), the trace of high-order term of the genetic relationship matrix, a component involved in the estimation procedure. In this study, we proposed two estimators, which can estimate tr( K T K ) with greatly reduced sampling variance compared to the existing method under the same computational complexity. We applied this method to 81 traits in UK Biobank data and compared the chromosome-wise partition heritability with the whole-genome heritability, also as an approach for testing polygenicity.

EigenGWAS: An online visualizing and interactive application for detecting genomic signatures of natural selection.

Detecting genetic regions under selection in structured populations is of great importance in ecology, evolutionary biology and breeding programmes. We recently proposed EigenGWAS, an unsupervised genomic scanning approach that is similar to F ST but does not require grouping information of the population, for detection of genomic regions under selection. The original EigenGWAS is designed for the random mating population, and here we extend its use to inbred populations. We also show in theory and simulation that eigenvalues, the previous corrector for genetic drift in EigenGWAS, are overcorrected for genetic drift, and the genomic inflation factor is a better option for this adjustment. Applying the updated algorithm, we introduce the new EigenGWAS online platform with highly efficient core implementation. Our online computational tool accepts plink data in a standard binary format that can be easily converted from the original sequencing data, provides the users with graphical results via the R-Shiny user-friendly interface. We applied the proposed method and tool to various data sets, and biologically interpretable results as well as caveats that may lead to an unsatisfactory outcome are given. The EigenGWAS online platform is available at www.eigengwas.com, and can be localized and scaled up via R (recommended) or docker.

Short-term pretreatment with atorvastatin attenuates left ventricular dysfunction, reduces infarct size and apoptosis in acute myocardial infarction rats.

BACKGROUND: Atorvastatin showed a number of cardiovascular benefits, however, the role and underlying molecular mechanisms of short-term atorvastatin-mediated protection remain unclear. METHODS: 30 rats were randomly divided into 3 groups: sham group, acute myocardial infarction model group and atorvastatin group. The rats of acute myocardial infarction model were established by ligation of the left anterior descending of coronary arteries. Before surgery, rats in the atorvastatin group received 20 mg/kg/d atorvastatin for 7 days in atorvastatin group. After 4 hours of model established, changes in hemodynamics parameters were recorded and myocardial infarct size was achieved by Evans blue-TTC staining. Myocardium apoptosis was evaluated by TUNEL. The expression of FAS, FAS-L, Bcl-2, Bax, p-BAD, Caspase-8 and Caspase-3 in myocardium were examined by Western blot. RESULTS: In the atorvastatin group, left ventricular function was elevated and infarct size was decreased compared with the model group. Moreover, in the atorvastatin group, the cell apoptosis index was reduced in response to myocardial infarction. The expressions of Bcl-2 were increased and Bax, p-BAD, Fas, Fas-L, caspase-8 and caspase-3 in myocardium were decreased in atorvastatin group. CONCLUSIONS: Short-term atorvastatin pretreatment restored left ventricular function and limited infarct size in acute myocardial infarction, which were associated with reduction of the apoptosis in myocardium through Bcl-2 and Fas pathway.