Identifying the Lipidomic Effects of a Rare Loss-of-Function Deletion in ANGPTL3

Background - The identification and understanding of therapeutic targets for atherosclerotic cardiovascular disease (ASCVD) is of fundamental importance given its global health and economic burden. Inhibition of angiopoietin-like 3 (ANGPTL3) has demonstrated a cardioprotective effect, showing promise for ASCVD treatment, and is currently the focus of ongoing clinical trials. Here we assessed the genetic basis of variation in ANGPTL3 levels in the San Antonio Family Heart Study. Methods - We assayed ANGPTL3 protein levels in ~1,000 Mexican Americans from extended pedigrees. By drawing upon existing plasma lipidome profiles and genomic data we conducted analyses to understand the genetic basis to variation in ANGPTL3 protein levels, and accordingly the correlation with the plasma lipidome. Results - In a variance components framework we identified that variation in ANGPTL3 was significantly heritable (h 2 =0.33, P=1.31×10 -16 ). To explore the genetic basis of this heritability, we conducted a genome-wide linkage scan and identified significant linkage (LOD = 6.18) to a locus on chromosome 1 at 90 cM, corresponding to the ANGPTL3 gene location. In the genomes of 23 individuals from a single pedigree, we identified a loss of function (LoF) variant, rs398122988 (N121Kfs*2), in ANGPTL3 , that was significantly associated with lower ANGPTL3 levels (β=−1.69 SDU, P=3.367×10 -13 ), and accounted for the linkage signal at this locus. Given the known role of ANGPTL3 as an inhibitor of endothelial and lipoprotein lipase we explored the association of ANGPTL3 protein levels and rs398122988 with the plasma lipidome and related phenotypes, identifying novel associations with phosphatidylinositols. Conclusions - Variation in ANGPTL3 protein levels is heritable and under significant genetic control. Both ANGPTL3 levels and LoF variants in ANGPTL3 have significant associations with the plasma lipidome. These findings further our understanding of ANGPTL3 as a therapeutic target for ASCVD.

Genome-wide analysis of high-risk primary brain cancer pedigrees identifies PDXDC1 as a candidate brain cancer predisposition gene

Background There is evidence for an inherited contribution to primary brain cancer. Linkage analysis of high-risk brain cancer pedigrees has identified candidate regions of interest in which brain cancer predisposition genes are likely to reside. Methods Genome-wide linkage analysis was performed in a unique set of 11 informative, extended, high-risk primary brain cancer pedigrees identified in a population genealogy database, which include from 2 to 6 sampled, related primary brain cancer cases. Access to formalin-fixed paraffin embedded tissue samples archived in a biorepository allowed analysis of extended pedigrees. Results Individual high-risk pedigrees were singly informative for linkage at multiple regions. Suggestive evidence for linkage was observed on chromosomes 2, 3, 14, and 16. The chromosome 16 region in particular contains a promising candidate gene, pyridoxal-dependent decarboxylase domain-containing 1 (PDXDC1), with prior evidence for involvement with glioblastoma from other previously reported experimental settings, and contains the lead single nucleotide polymorphism (rs3198697) from the linkage analysis of the chromosome 16 region. Conclusions Pedigrees with a statistical excess of primary brain cancers have been identified in a unique genealogy resource representing the homogeneous Utah population. Genome-wide linkage analysis of these pedigrees has identified a potential candidate predisposition gene, as well as multiple candidate regions that could harbor predisposition loci, and for which further analysis is suggested.

Dog10K: an international sequencing effort to advance studies of canine domestication, phenotypes and health

ABSTRACT Dogs are the most phenotypically diverse mammalian species, and they possess more known heritable disorders than any other non-human mammal. Efforts to catalog and characterize genetic variation across well-chosen populations of canines are necessary to advance our understanding of their evolutionary history and genetic architecture. To date, no organized effort has been undertaken to sequence the world's canid populations. The Dog10K Consortium (http://www.dog10kgenomes.org) is an international collaboration of researchers from across the globe who will generate 20× whole genomes from 10 000 canids in 5 years. This effort will capture the genetic diversity that underlies the phenotypic and geographical variability of modern canids worldwide. Breeds, village dogs, niche populations and extended pedigrees are currently being sequenced, and de novo assemblies of multiple canids are being constructed. This unprecedented dataset will address the genetic underpinnings of domestication, breed formation, aging, behavior and morphological variation. More generally, this effort will advance our understanding of human and canine health.

Detection of rare disease variants in extended pedigrees using RVS

Summary Family-based sequencing studies enable researchers to identify highly penetrant genetic variants too rare to be tested in conventional case-control studies, by studying co-segregation of variant and disease phenotypes. When multiple affected subjects in a family are sequenced, the probability that a variant or a set of variants is shared identical-by-descent by some or all affected relatives provides evidence against the null hypothesis of complete absence of linkage and association. The Rare Variant Sharing software package RVS implements a suite of tools to assess association and linkage between rare genetic variants and a dichotomous disease indicator in family pedigrees. Availability and Implementation RVS is available as open source software from the Bioconductor webpage at https://bioconductor.org/packages/release/bioc/html/RVS.html. Supplementary information Supplementary data are available at Bioinformatics online.

A novel nonsense variant in SUPT20H gene associated with Rheumatoid Arthritis identified by Whole Exome Sequencing of multiplex families

The triggering and development of Rheumatoid Arthritis (RA) is conditioned by environmental and genetic factors. Despite the identification of more than one hundred genetic variants associated with the disease, not all the cases can be explained. Here, we performed Whole Exome Sequencing in 9 multiplex families (N=30) to identify rare variants susceptible to play a role in the disease pathogenesis. We pre-selected 73 genes which carried rare variants with a complete segregation with RA in the studied families. Follow-up linkage and association analyses with pVAAST highlighted significant RA association of 24 genes (p-value < 0.05 after 106 permutations) and pinpointed their most likely causal variant. We re-sequenced the 10 most significant likely causal variants (p-value ≤ 0.019 after 106 permutations) in the extended pedigrees and 9 additional multiplex families (N=110). Only one SNV in SUPT20H, c.73T>A (p.Lys25*), presented a complete segregation with RA in an extended pedigree with early-onset cases. In summary, we identified in this study a new variant associated with RA in SUPT20H gene. This gene belongs to several biological pathways like macro-autophagy and monocyte/macrophage differentiation, which contribute to RA pathogenesis. In addition, these results showed that analyzing rare variants using a family-based approach is a strategy that allows to identify RA risk loci, even with a small dataset.Author summaryRheumatoid arthritis (RA) is one of the most frequent auto-immune disease in the world. It causes joint swellings and pains which can lead to mobility impairment. To date, the scientific community has identified a hundred genes carrying variants predisposing to RA, in addition to the major gene HLA-DRB1. However, they do not explain all cases of RA. By examining nine families with multiple RA cases, we identified a new rare nonsense variant in SUPT20H gene, c.73T>A (p.Lys25*). This finding is supported by the literature as the SUPT20H gene regulates several biological functions, such as macro-autophagy or monocyte/macrophage differentiation, that contribute to RA pathogenesis.