Social and structural changes in Russia: problems and prospects

This article is devoted to a review and general analysis of the main social trends in modern Russian society. In particular, the authors analyze statistical data on the most pressing problems of modern society, in parallel, attention is paid to assessing social trends in a number of the most painful issues, such as: vocational education and employment of the population, stratification of society, labor migration, demographic composition of society, demographic dynamics, processes, social consent and civic engagement of the population.

The unrecognized potential of pet cats for studying aging and age-related diseases

Old cats develop chronic diseases similar to diseases in older people. One-fourth of American households own cats, and almost half are more than 7 years old. Cats share the same environment and are exposed to many of the same chemical stresses. In addition, genomic diversity and population stratification are similar to that occurring in people. With these comparative features, the aging cat represents a geroscience model to investigate the pathogenesis and therapeutic interventions for aging. However, cats are generally not recognized as a translational model for aging research mainly because of the lack of knowledge and appreciation within the scientific community. In addition, cat owners are not aware of any research programs designed to enhance healthy aging in their pets because none exist. Much work is needed to inform and educate the scientific community as well as cat owners about the power of aging cats as a transformative model to investigate aging and age-related diseases that will benefit both human and feline health. Keywords: Aging cats, age-related diseases, healthy aging, geroscience

Genetic diversity of ‘Very Important Pharmacogenes’ in two South-Asian populations

Objectives Reliable identification of population-specific variants is important for building the single nucleotide polymorphism (SNP) profile. In this study, genomic variation using allele frequency differences of pharmacologically important genes for Gujarati Indians in Houston (GIH) and Indian Telugu in the U.K. (ITU) from the 1000 Genomes Project vis-à-vis global population data was studied to understand its role in drug response. Methods Joint genotyping approach was used to derive variants of GIH and ITU independently. SNPs of both these populations with significant allele frequency variation (minor allele frequency ≥ 0.05) with super-populations from the 1000 Genomes Project and gnomAD based on Chi-square distribution with p-value of ≤ 0.05 and Bonferroni’s multiple adjustment tests were identified. Population stratification and fixation index analysis was carried out to understand genetic differentiation. Functional annotation of variants was carried out using SnpEff, VEP and CADD score. Results Population stratification of VIP genes revealed four clusters viz., single cluster of GIH and ITU, one cluster each of East Asian, European, African populations and Admixed American was found to be admixed. A total of 13 SNPs belonging to ten pharmacogenes were identified to have significant allele frequency variation in both GIH and ITU populations as compared to one or more super-populations. These SNPs belong to VKORC1 (rs17708472, rs2359612, rs8050894) involved in Vitamin K cycle, cytochrome P450 isoforms CYP2C9 (rs1057910), CYP2B6 (rs3211371), CYP2A2 (rs4646425) and CYP2A4 (rs4646440); ATP-binding cassette (ABC) transporter ABCB1 (rs12720067), DPYD1 (rs12119882, rs56160474) involved in pyrimidine metabolism, methyltransferase COMT (rs9332377) and transcriptional factor NR1I2 (rs6785049). SNPs rs1544410 (VDR), rs2725264 (ABCG2), rs5215 and rs5219 (KCNJ11) share high fixation index (≥ 0.5) with either EAS/AFR populations. Missense variants rs1057910 (CYP2C9), rs1801028 (DRD2) and rs1138272 (GSTP1), rs116855232 (NUDT15); intronic variants rs1131341 (NQO1) and rs115349832 (DPYD) are identified to be ‘deleterious’. Conclusions Analysis of SNPs pertaining to pharmacogenes in GIH and ITU populations using population structure, fixation index and allele frequency variation provides a premise for understanding the role of genetic diversity in drug response in Asian Indians.

Polygenic scores: prediction versus explanation

During the past decade, polygenic scores have become a fast-growing area of research in the behavioural sciences. The ability to directly assess people’s genetic propensities has transformed research by making it possible to add genetic predictors of traits to any study. The value of polygenic scores in the behavioural sciences rests on using inherited DNA differences to predict, from birth, common disorders and complex traits in unrelated individuals in the population. This predictive power of polygenic scores does not require knowing anything about the processes that lie between genes and behaviour. It also does not mandate disentangling the extent to which the prediction is due to assortative mating, genotype–environment correlation, or even population stratification. Although bottom-up explanation from genes to brain to behaviour will remain the long-term goal of the behavioural sciences, prediction is also a worthy achievement because it has immediate practical utility for identifying individuals at risk and is the necessary first step towards explanation. A high priority for research must be to increase the predictive power of polygenic scores to be able to use them as an early warning system to prevent problems.

Controlling for human population stratification in rare variant association studies

Population stratification is a confounder of genetic association studies. In analyses of rare variants, corrections based on principal components (PCs) and linear mixed models (LMMs) yield conflicting conclusions. Studies evaluating these approaches generally focused on limited types of structure and large sample sizes. We investigated the properties of several correction methods through a large simulation study using real exome data, and several within- and between-continent stratification scenarios. We considered different sample sizes, with situations including as few as 50 cases, to account for the analysis of rare disorders. Large samples showed that accounting for stratification was more difficult with a continental than with a worldwide structure. When considering a sample of 50 cases, an inflation of type-I-errors was observed with PCs for small numbers of controls (≤ 100), and with LMMs for large numbers of controls (≥ 1000). We also tested a novel local permutation method (LocPerm), which maintained a correct type-I-error in all situations. Powers were equivalent for all approaches pointing out that the key issue is to properly control type-I-errors. Finally, we found that power of analyses including small numbers of cases can be increased, by adding a large panel of external controls, provided an appropriate stratification correction was used.

Benchmarking statistical methods for analyzing parent-child dyads in genetic association studies

Genetic association studies of child health outcomes often employ family-based designs. One of the most popular family-based designs is the case-parent trio design that considers the smallest possible nuclear family consisting of two parents and their affected child. This trio design is particularly advantageous for studying relatively rare disorders because it is less prone to type 1 error inflation due to population stratification compared to population-based study designs (e.g., case-control studies). However, obtaining genetic data from both parents is difficult, from a practical perspective, and many large studies predominantly measure genetic variants in mother-child dyads. While some statistical methods for analyzing parent-child dyad data (most commonly involving mother-child pairs) exist, it is not clear if they provide the same advantage as trio methods in protecting against population stratification, or if a specific dyad design (e.g., case-mother dyads vs. case-mother/control-mother dyads) is more advantageous. In this article, we review existing statistical methods for analyzing genome-wide data on dyads and perform extensive simulation experiments to benchmark their type I errors and statistical power under different scenarios. We extend our evaluation to existing methods for analyzing a combination of case-parent trios and dyads together. We apply these methods on genotyped and imputed data from multi-ethnic mother-child pairs only, case-parent trios only or combinations of both dyads and trios from the Gene, Environment Association Studies consortium (GENEVA), where each family was ascertained through a child affected by nonsyndromic cleft lip with or without cleft palate. Results from the GENEVA study corroborate the findings from our simulation experiments. Finally, we provide recommendations for using statistical genetic association methods for dyads.

Implementing Privacy-Preserving Genotype Analysis with Consideration for Population Stratification

In bioinformatics, genome-wide association studies (GWAS) are used to detect associations between single-nucleotide polymorphisms (SNPs) and phenotypic traits such as diseases. Significant differences in SNP counts between case and control groups can signal association between variants and phenotypic traits. Most traits are affected by multiple genetic locations. To detect these subtle associations, bioinformaticians need access to more heterogeneous data. Regulatory restrictions in cross-border health data exchange have created a surge in research on privacy-preserving solutions, including secure computing techniques. However, in studies of such scale, one must account for population stratification, as under- and over-representation of sub-populations can lead to spurious associations. We improve on the state of the art of privacy-preserving GWAS methods by showing how to adapt principal component analysis (PCA) with stratification control (EIGENSTRAT), FastPCA, EMMAX and the genomic control algorithm for secure computing. We implement these methods using secure computing techniques—secure multi-party computation (MPC) and trusted execution environments (TEE). Our algorithms are the most complex ones at this scale implemented with MPC. We present performance benchmarks and a security and feasibility trade-off discussion for both techniques.