Biopankkitutkimukset – 2024

FinnGen is a 10-year study aiming to identify genetic risk factors for thousands of diseases. The third phase of the FinnGen study focuses on deeper analyses of diseases and genetic variants identified in the earlier phases without expanding the current cohort of 520,000 participants. The project will emphasize longitudinal studies of disease progression and therapeutic responses and explore the biological mechanisms of genetic signals in selected diseases. New health data and molecular profiling data will be integrated with the existing data to further boost our understanding of the biological processes underlying disease development in individuals with specific genetic variants. Proteins serve as vital biomarkers for diseases and drug responses, influenced by genetic, clinical, and environmental factors, and are essential for monitoring overall health. To enable proteomic analyses in FinnGen, we will produce proteomic data from selected EDTA plasma samples collected by the Finnish biobanks. We will test whether the Finnish-enriched disease-associated variants have an impact on the plasma protein profile. These analyses can help us to understand which genetically identified targets may be suitable for halting or slowing disease progression and further enhance novel drug development and precision medicine applications.

FinnGen is a 10-year study aiming to identify genetic risk factors for thousands of diseases. The third phase of the FinnGen study focuses on deeper analyses of diseases and genetic variants identified in the earlier phases without expanding the current cohort of 520,000 participants. The project will emphasize longitudinal studies of disease progression and therapeutic responses and explore the biological mechanisms of genetic signals in selected diseases. New health data and molecular profiling data will be integrated with the existing data to further boost our understanding of the biological processes underlying disease development in individuals with specific genetic variants. In this FinnGen sub-effort, we aim to identify rare variants that contribute to bipolar disorder and severe eating disorders by exome sequencing approximately 12,000 FinnGen participants. Current knowledge indicates that mental health disorders have a polygenic genetic background. In addition to a combined effect of many minor genetic risk factors (polygenic risk), sequencing studies have identified rare coding variants with a larger impact on disease risk. Despite their rarity, these variants are important for understanding the biological mechanisms that lead to disease susceptibility, potentially opening up new opportunities for functional studies and novel treatment options.

FinnGen is a 10-year study aiming to identify genetic risk factors for thousands of diseases. The third phase of the FinnGen study focuses on deeper analyses of diseases and genetic variants identified in the earlier phases without expanding the current cohort of 520,000 participants. The project will emphasize longitudinal studies of disease progression and therapeutic responses and explore the biological mechanisms of genetic signals in selected diseases. New health data and molecular profiling data will be integrated with the existing data to further boost our understanding of the biological processes underlying disease development in individuals with specific genetic variants. In this FinnGen sub-effort, we aim to better understand the genetic background of the most common form of polycystic kidney disease, ADPKD. It affects about 1 in 400 to 1,000 people and is primarily caused by mutations in the PKD1 and PKD2 genes. Patients are usually diagnosed in adulthood and face risks like kidney failure, hypertension, and pain. To identify the key factors in ADPKD progression, it is important to know what kind of highly penetrant risk variants contributing to disease susceptibility the patients have. For this, the GWAS-based genotype data currently available in FinnGen is insufficient and thus we will perform exome sequencing on ~800 potential ADPKD cases.

The surge in Alzheimer's disease (AD) blood biomarker research, especially following Leqembi's FDA approval, underscores the urgent need for more specific diagnostic tools. Traditional biomarkers like amyloid PET scans and CSF Aβ42 or pTau assays effectively predict cerebral amyloid plaques but lack specificity in forecasting which Mild Cognitive Impairment (MCI) patients will develop AD dementia symptoms (Ritchie et al., 2014). Developing biomarkers beyond those that predict high amyloid plaque levels remains challenging. Consequently, AD diagnostic companies focus on incremental innovations, striving for less invasive methods than amyloid PET or CSF testing, yet still encountering specificity limitations in predicting which MCI patients will develop AD dementia symptoms in the coming years (Souchet et al., 2023).

Current approaches measure biomarkers such as Aβ42, Aβ40, pTau181, or pTau217 in plasma, but these do not outperform more invasive methods like CSF assays (Ashton et al., 2024). A recent study on the pTau217 biomarker revealed that 53.7% of (pTau217)-positive MCI patients did not develop AD dementia symptoms within three years, underscoring this specificity problem (Lehmann et al., 2024).

AgenT has pioneered an innovative approach using AAV-AD rats (Audrain et al., 2018) to discover blood biomarkers that predict the conversion to AD dementia symptoms, rather than the presence of cerebral amyloid plaques. After extensive research and a multicentric retrospective study on 632 individuals, AgenT identified a panel of highly specific biomarkers and validated two blood tests, B-HEALED (Souchet et al., 2024) and B-AHEAD. These tests are designed to select individuals who will develop AD dementia symptoms from MCI patients and cognitively normal individuals, respectively. The novelty of this methodology lies in combining these biomarkers through machine learning to capture the AD biological complexity. This approach offers a more specific diagnostic tool, potentially transforming early AD detection and intervention.

The primary objective of this collaboration between AgenT and Finnish Biobanks is to quantify multiomics biomarkers in biobanked plasma samples. The analysis and quantifications are part of a larger effort to validate the version II of B-HEALED and B-AHEAD blood tests. Finnish Biobanks will provide the plasma samples and associated clinical data for the study.

Alzheimerin tauti ja otsaohimolohkorappeumat on kansantaloudellisesti merkittäviä dementiaan johtavia hermostoa rappeuttavia sairauksia. Hankkeessa pyritään ymmärtämään mikrogliasolujen solutason mekanismeja hermoston rappeutumisessa. Hankkeessa keskitytään tiettyihin muutoksiin C9ORF72- sekä TYROBP-geeneissä, jotka säätelevät sairastumisriskiä Alzheimerin taudissa ja otsaohimolohkorappeumissa, ja niiden toistaiseksi tuntemattomaan mekanistiseen rooliin mikrogliasoluissa hyödyntäen genomisia tutkimusmenetelmiä. Saatua tietoa mikrogliasolujen solutason mekanismeista hyödynnetään jatkossa yksilöllistetyn lääketieteen sovellutuksissa ennakoivien biomarkkereiden löytämiseksi sekä uusien hoitojen kehittämiseksi.