A Pipeline for Phasing and Genotype Imputation on Mixed Human Data (Parents-Offspring Trios and Unrelated Subjects) by Reviewing Current Methods and Software

Genotype imputation has become an essential prerequisite when performing association analysis. It is a computational technique that allows us to infer genetic markers that have not been directly genotyped, thereby increasing statistical power in subsequent association studies, which consequently has a crucial impact on the identification of causal variants. Many features need to be considered when choosing the proper algorithm for imputation, including the target sample on which it is performed, i.e., related individuals, unrelated individuals, or both. Problems could arise when dealing with a target sample made up of mixed data, composed of both related and unrelated individuals, especially since the scientific literature on this topic is not sufficiently clear. To shed light on this issue, we examined existing algorithms and software for performing phasing and imputation on mixed human data from SNP arrays, specifically when related subjects belong to trios. By discussing the advantages and limitations of the current algorithms, we identified LD-based methods as being the most suitable for reconstruction of haplotypes in this specific context, and we proposed a feasible pipeline that can be used for imputing genotypes in both phased and unphased human data

Heritability Estimation of Multiple Sclerosis Related Plasma Protein Levels in Sardinian Families with Immunochip Genotyping Data

This work aimed at estimating narrow-sense heritability, defined as the proportion of the phenotypic variance explained by the sum of additive genetic effects, via Haseman-Elston regression for a subset of 56 plasma protein levels related to Multiple Sclerosis (MS). These were measured in 212 related individuals (with 69 MS cases and 143 healthy controls) obtained from 20 Sardinian families with MS history. Using pedigree information, we found seven statistically significant heritable plasma protein levels (after multiple testing correction), i.e., Gc (h(2) = 0.77; 95%CI: 0.36, 1.00), Plat (h(2) = 0.70; 95%CI: 0.27, 0.95), Anxa1 (h(2) = 0.68; 95%CI: 0.27, 1.00), Sod1 (h(2) = 0.58; 95%CI: 0.18, 0.96), Irf8 (h(2) = 0.56; 95%CI: 0.19, 0.99), Ptger4 (h(2) = 0.45; 95%CI: 0.10, 0.96), and Fadd (h(2) = 0.41; 95%CI: 0.06, 0.84). A subsequent analysis was performed on these statistically significant heritable plasma protein levels employing Immunochip genotyping data obtained in 155 healthy controls (92 related and 63 unrelated); we found a meaningful proportion of heritable plasma protein levels' variability explained by a small set of SNPs. Overall, the results obtained, for these seven MS-related proteins, emphasized a high additive genetic variance component explaining plasma levels' variability