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Approved Research

Neurological and psychiatric impact of indel mutations in amino acid repeat (AAR)-encoding regions of neural genes

Principal Investigator: Dr Ferdinando Fiumara
Approved Research ID: 71453
Approval date: October 26th 2021

Lay summary

The genetic basis of the physiological and pathological phenotypes in humans is only partially understood despite the increasing availability of genomic DNA sequencing. Current genomic studies typically aim at relating changes of single 'letters', i.e. nucleotides, in the DNA sequence, the so-called single nucleotide polymorphisms (SNPs), with physiological traits and disease predispositions. However, these studies can explain only part of the observed genetic heritability of physiological and pathological phenotypes in humans. Thus, alternative approaches are required to overcome this 'missing heritability' issue. Emerging evidence, including the results of our ongoing research, indicates the possibility that non-SNP mutations of the DNA may have a considerable phenotypic impact. This type of mutations leads, rather than to the change of one single 'letter' into another in the DNA sequence, to the insertion or deletion (or 'indel') of repetitive blocks of three 'letters' (or 'triplets') in certain genes, leading to the elongation/contraction of amino acid repeats (AARs) in proteins coded by the same genes.

Remarkably, AARs are frequently found in proteins with important roles in the nervous system, and their indel-related length variation has been linked to the modulation of neuropsychiatric traits and to neurodegenerative diseases such as Huntington disease.

Leveraging the unique genetic and phenotypic datasets of the UK Biobank, our research aims at identifying the pathophysiological impact on the nervous system of genetic mutations changing the length of AARs in neural proteins. We will determine, for subjects in the UK Biobank database, both the AAR length repertoire in neural genes of interest, selected based on our previous analyses, and available parameters related to neuropsychiatric traits and disorders, including neuroimaging data. This analysis will be carried out using a multidisciplinary approach that will integrate the specific competences of our group in neuroscience, genomics, and bioinformatics.

Ultimately, this project will relate quantitatively indel-related AAR length variation in neural proteins with neuropsychiatric and neuroanatomical phenotypes. This investigation meets the fundamental commitments of the UK Biobank as it deals with important health-related issues, such as the genetic basis of the function, dysfunction and degeneration of the nervous system, with a profound societal impact especially in aging populations.