Biosystems and Integrative Sciences Institute

Funder

Organizational Unit

Publications

Biomedical knowledge graph embeddings for personalized medicine: Predicting disease‐gene associations

Publication . Vilela, Joana; Asif, Muhammad; Marques, Ana Rita; Santos, João Xavier; Rasga, Célia; Vicente, Astrid; Martiniano, Hugo

Personalized medicine is a concept that has been subject of increasing interest in medical research and practice in the last few years. However, significant challenges stand in the way of practical implementations, namely in regard to extracting clinically valuable insights from the vast amount of biomedical knowledge generated in the last few years. Here, we describe an approach that uses Knowledge Graph Embedding (KGE) methods on a biomedical Knowledge Graph (KG) as a path to reasoning over the wealth of information stored in publicly accessible databases. We built a Knowledge Graph using data from DisGeNET and GO, containing relationships between genes, diseases and other biological entities. The KG contains 93,657 nodes of 5 types and 1,705,585 relationships of 59 types. We applied KGE methods to this KG, obtaining an excellent performance in predicting gene-disease associations (MR 0.13, MRR 0.96, HITS@1 0.93, HITS@3 0.99, and HITS@10 0.99). The optimal hyperparameter set was used to predict all possible novel gene-disease associations. An in-depth analysis of novel gene-disease predictions for disease terms related to Autism Spectrum Disorder (ASD) shows that this approach produces predictions consistent with known candidate genes and biological pathways and yields relevant insights into the biology of this paradigmatic complex disorder.

2022-11-20Journal article

Open access

Publication . Vilela, Joana; Martiniano, Hugo; Marques, Ana Rita; Santos, João Xavier; Rasga, Célia; Oliveira, Guiomar; Vicente, Astrid Moura

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with heterogeneous clinical presentation, variable severity, and multiple comorbidities. A complex underlying genetic architecture matches the clinical heterogeneity, and evidence indicates that several co-occurring brain disorders share a genetic component with ASD. In this study, we established a genetic similarity disease network approach to explore the shared genetics between ASD and frequent comorbid brain diseases (and subtypes), namely Intellectual Disability, Attention-Deficit/Hyperactivity Disorder, and Epilepsy, as well as other rarely co-occurring neuropsychiatric conditions in the Schizophrenia and Bipolar Disease spectrum. Using sets of disease-associated genes curated by the DisGeNET database, disease genetic similarity was estimated from the Jaccard coefficient between disease pairs, and the Leiden detection algorithm was used to identify network disease communities and define shared biological pathways. We identified a heterogeneous brain disease community that is genetically more similar to ASD, and that includes Epilepsy, Bipolar Disorder, Attention-Deficit/Hyperactivity Disorder combined type, and some disorders in the Schizophrenia Spectrum. To identify loss-of-function rare de novo variants within shared genes underlying the disease communities, we analyzed a large ASD whole-genome sequencing dataset, showing that ASD shares genes with multiple brain disorders from other, less genetically similar, communities. Some genes (e.g., SHANK3, ASH1L, SCN2A, CHD2, and MECP2) were previously implicated in ASD and these disorders. This approach enabled further clarification of genetic sharing between ASD and brain disorders, with a finer granularity in disease classification and multi-level evidence from DisGeNET. Understanding genetic sharing across disorders has important implications for disease nosology, pathophysiology, and personalized treatment.

2022-08-18Journal article

Open access

Brown Algae Potential as a Functional Food against Hypercholesterolemia: Review

Publication . André, Rebeca; Pacheco, Rita; Bourbon, Mafalda; Serralheiro, Maria Luísa

Brown algae have been part of the human diet for hundreds of years, however, in recent years, commercial and scientific interest in brown algae has increased due to the growing demand for healthier diet by the world population. Brown algae and its metabolites, such as carotenoids, polysaccharides, phlorotannins, and proteins, have been associated with multiple beneficial health effects for different diseases, such as cardiovascular diseases, one of the main causes of death in Europe. Since high blood cholesterol levels are one of the major cardiovascular risks, this review intends to provide an overview of current knowledge about the anti-hypercholesterolemic effect of different brown algae species and/or their isolated compounds.

2021-01-24Journal article

Open access

Functional characterization of variants in the 5’UTR and promoter of PCSK9 gene

Publication . Alves, Ana Catarina; Fernandes, Rafael; Menezes, Juliane; Romão, Luísa; Bourbon, Mafalda

Familial hypercholesterolemia (FH) is the most common genetic disorder conferring an increased cardiovascular risk due to cholesterol accumulation since birth. The majority of patients with FH phenotype have mutations in LDLR, APOB or PCSK9 genes. In about 50% of patients a variant causing disease has not been possible to find. The 5' and 3’ untranslated regions (UTRs) and promoter of these genes is poorly studied. Consequently, few variants were detected in these locations and functional validation is lacking for the ones described. The aim of this project is to perform an in vitro characterization of variants in 5’ UTR and promoter of PCSK9 gene.

2021-08Conference object

Restricted access