The identification and characterisation of genomic changes (variants) that can lead to human diseases is one of the central aims of biomedical research. The generation of catalogues of genetic variants that have an impact on specific diseases is the basis of Personalised Medicine, where diagnoses and treatment protocols are selected according to each patient’s profile. In this context, the study of complex diseases, such as Type 2 diabetes or cardiovascular alterations, is fundamental. However, these diseases result from the combination of multiple genetic and environmental factors, which makes the discovery of causal variants particularly challenging at a statistical and computational level. Genome-Wide Association Studies (GWAS), which are based on the statistical analysis of genetic variant frequencies across non-diseased and diseased individuals, have been successful in finding genetic variants that are associated to specific diseases or phenotypic traits. But GWAS methodology is limited when considering important genetic aspects of the disease and has not yet resulted in meaningful translation to clinical practice. This review presents an outlook on the study of the link between genetics and complex phenotypes. We first present an overview of the past and current statistical methods used in the field. Next, we discuss current practices and their main limitations. Finally, we describe the open challenges that remain and that might benefit greatly from further mathematical developments.

The use of large-scale supercomputing architectures is a hard requirement for scientific computing Big-Data applications. An example is genomics analytics, where millions of data transformations and tests per patient need to be done to find relevant clinical indicators. Therefore, to ensure open and broad access to high-performance technologies, governments, and academia are pushing toward the introduction of novel computing architectures in large-scale scientific environments. This is the case of RISC-V, an open-source and royalty-free instruction-set architecture. To evaluate such technologies, here we present the Variant-Interaction Analytics use case benchmarking suite and datasets. Through this use case, we search for possible genetic interactions using computational and statistical methods, providing a representative case for heavy ETL (Extract, Transform, Load) data processing. Current implementations are implemented in x86-based supercomputers (e.g. MareNostrum-IV at the Barcelona Supercomputing Center (BSC)), and future steps propose RISC-V as part of the next MareNostrum generations. Here we describe the Variant Interaction Use Case, highlighting the characteristics leveraging high-performance computing, indicating the caveats and challenges towards the next RISC-V developments and designs to come from a first comparison between x86 and RISC-V architectures on real Variant Interaction executions over real hardware implementations.

One of the main goals of human genetics is to understand the connections between genomic variation and the predisposition to develop a complex disorder. These disease–variant associations are usually studied in a single independent manner, disregarding the possible effect derived from the interaction between genomic variants. In particular, in a background of complex diseases, these interactions can be directly linked to the disorder and may play an important role in disease development. Although their study has been suggested to help complete the understanding of the genetic bases of complex diseases, this still represents a big challenge due to large computing demands. Here, we take advantage of high-performance computing technologies to tackle this problem by using a combination of machine learning methods and statistical approaches. As a result, we created a containerized framework that uses multifactor dimensionality reduction (MDR) to detect pairs of variants associated with type 2 diabetes (T2D). This methodology was tested on the Northwestern University NUgene project cohort using a dataset of 1,883,192 variant pairs with a certain degree of association with T2D. Out of the pairs studied, we identified 104 significant pairs: two of which exhibit a potential functional relationship with T2D. These results place the proposed MDR method as a valid, efficient, and portable solution to study variant interaction in real reduced genomic datasets.