Efficient Differentially Private Methods for a Transmission Disequilibrium Test in Genome Wide Association Studies

To achieve the provision of personalized medicine, it is very important to investigate the relationship between diseases and human genomes. For this purpose, large-scale genetic studies such as genome-wide association studies are often conducted, but there is a risk of identifying individuals if the statistics are released as they are. In this study, we propose new efficient differentially private methods for a transmission disequilibrium test, which is a family-based association test. Existing methods are computationally intensive and take a long time even for a small cohort. Moreover, for approximation methods, sensitivity of the obtained values is not guaranteed. We present an exact algorithm with a time complexity of 𝒪(nm) for a dataset containing n families and m single nucleotide polymorphisms (SNPs). We also propose an approximation algorithm that is faster than the exact one and prove that the obtained scores’ sensitivity is 1. From our experimental results, we demonstrate that our exact algorithm is 10, 000 times faster than existing methods for a small cohort with 5, 000 SNPs. The results also indicate that the proposed method is the first in the world that can be applied to a large cohort, such as those with 106 SNPs. In addition, we examine a suitable dataset to apply our approximation algorithm. Supplementary materials are available at https://github.com/ay0408/DP-trio-TDT.

Family-Based Cohort Association Study of PRKCB1, CBLN1 and KCNMB4 Gene Polymorphisms and Autism in Polish Population

The aim of the study was to perform family-based association analysis of PRKCB1, CBLN1 and KCNMB4 gene polymorphisms and autism disorder. We comprised 206 Caucasian children with autistic spectrum disorder (ASD) and their biological parents. In transmission/disequilibrium test we observed that T-allele of the rs198198 polymorphism of the PRKCB1 gene was more often transmitted to affected children in the male subgroup (p = 0.010). Additionally, the T carrier state was significantly associated with hypotonia (p = 0.048). In the female subgroup, the T-allele carriers more often showed more mobile/vital behavior (p = 0.046). In conclusion, our study showed that the rs198198 of the PRKCB1 gene may be associated with ASD in men and with some features characteristic for the disorder.

Causal inference in genetic trio studies

We introduce a method to draw causal inferences—inferences immune to all possible confounding—from genetic data that include parents and offspring. Causal conclusions are possible with these data because the natural randomness in meiosis can be viewed as a high-dimensional randomized experiment. We make this observation actionable by developing a conditional independence test that identifies regions of the genome containing distinct causal variants. The proposed digital twin test compares an observed offspring to carefully constructed synthetic offspring from the same parents to determine statistical significance, and it can leverage any black-box multivariate model and additional nontrio genetic data to increase power. Crucially, our inferences are based only on a well-established mathematical model of recombination and make no assumptions about the relationship between the genotypes and phenotypes. We compare our method to the widely used transmission disequilibrium test and demonstrate enhanced power and localization.