Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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Gewählte Publikation:

Gampawar, P.
Genetic determinants of brain ageing.
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2020. pp. 114 [OPEN ACCESS]


Autor*innen der Med Uni Graz:
Gampawar Piyush Gajananrao
Schmidt Helena
Schmidt Reinhold

The general aim of this thesis was to contribute to a better understanding of brain ageing using genetic epidemiological approaches. We specifically focused on 2 aims 1) exploring the role of leukocyte telomere length (LTL) a marker of cellular senescence in structural and functional alteration of the brain during ageing and 2) establishing robust high validity protocols for whole exome/genome sequencing (WES/WGS) and genomic databases based on WES/WGS data generated in our cohorts. These accomplishments form the basis for further studies dissecting the pathomechanism of brain ageing. The 2 aims are presented in Part I and Part II. In detail in Part I, we first explored the association between LTL, and global MRI markers of brain ageing such as brain parenchymal fraction (BPF) and white matter hyperintensities (WMH) as well as cognitive functions within the Austrian Stroke Prevention Study (ASPS) (N=909; age=65.9±8.0; female=57.3%). MRIs was done on a 1.5T scanner and LTL measurements using RT-PCR. Longer LTL was significantly associated with larger BPF (ß=0.43, p < 0.001), larger WMH (ß=0.03, p=0.04) and better performance in the attention/speed domain. The effect was confined to those overweight (BMI ≥25, ß=0.04, p=0.05) and with lower education (≤10 years, ß=0.04, p=0.05). Importantly, the beneficial effect of longer LTL on attention/speed was partly mediated by BPF in both subgroups (ß= 0.02, 95%CI=0.01-0.03). Our results support a strong protective role of longer LTL on the brain especially in the presence of risk factors. In order to follow up on these findings we next initiated a collaboration within the JPND BRIDGET consortium. In frame of this initiative, we conducted a pilot study on 90 participants of the Graz Study Health & Aging (GSHA) (age=67.6±9.0; female=63.3%). Our pilot study provided a proof of principle that LTL extracted from WGS data using the TelSeq software can be used to generate and combine LTL data from the various cohorts within BRIDGET. The use of the combined data provides several advantages 1) increases the sample size to >2000, 2) assessing the effect of LTL at the microstructural level of the brain, and 3) investigating the effect of LTL on the brain over a much wider age range (20->90ys). In Part II of this thesis, we present the evaluation of 2 library preparation methods for WES namely AmpliSeq and SureSelect and an improved variant calling protocol for Ion Proton. We used 12 in-house DNAs and the NA12878 reference DNA. We found comparable sensitivity (93%) but a higher positive predictive value (PPV) for AmpliSeq than SureSelect (84%vs80%). Our improved protocol substantially reduced false positives by 90% and increased PPV to 97%. As WGS became available as part of the BRIDGET collaboration, we selected in total 150 ASPS family and GSHA participants to be sequenced on Illumina HiSeq at the McGill Genomic Centre. The joint variant calling and quality control has been completed and a study is ongoing to identify rare genetic variants associated with structural markers of brain ageing. In summary, we show that longer LTL is associated with larger brain size which in turn transfers to better cognitive performance in the attention/speed domain. Importantly, longer LTL is especially beneficial in the presence of risk factors such as overweight and low education. In order to follow-up on these findings we initiated a collaborative study using LTL extracted from WGS in frame of the BRIDGET consortium. Further on we established several resources including high validity NGS protocol on Ion Proton and comprehensive databases of genomic variants derived from WES, WGS in our cohorts.

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