Biobank-based genetic characterization of neurodegenerative diseases and idiopathic normal pressure hydrocephalus: insights and lessons learned from FinnGen.
Source: PubMed, NCBI / U.S. National Library of Medicine
Brain disorders characterized by progressive neurodegeneration, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), represent an increasing medical and societal challenge. While genome‑wide studies have uncovered numerous susceptibility loci, these efforts have largely focused on common variants and leave a substantial portion of genetic liability unresolved. Variants of low frequency, often associated with stronger biological effects, remain insufficiently characterized, particularly in heterogeneous populations. Genetically isolated populations offer an effective strategy to overcome these limitations. Finland, shaped by historical demographic events, harbors a distinctive spectrum of enriched rare variants that can facilitate gene discovery. The FinnGen initiative capitalizes on this setting by combining extensive genotyping with nationwide health registry data through a coordinated network of Finnish biobanks. With half a million participants analyzed, FinnGen supports highly powered analyses across a broad array of clinical outcomes and registry data. Recent comprehensive analyses have reported thousands of significant genotype-phenotype associations, including novel protein‑altering variants. Importantly, the FinnGen cohort structure favors older individuals and hospital‑derived samples, increasing representation of brain disorders, such as AD and idiopathic normal pressure hydrocephalus (iNPH), a disorder frequently accompanied by A
Abstract
Brain disorders characterized by progressive neurodegeneration, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), represent an increasing medical and societal challenge. While genome‑wide studies have uncovered numerous susceptibility loci, these efforts have largely focused on common variants and leave a substantial portion of genetic liability unresolved. Variants of low frequency, often associated with stronger biological effects, remain insufficiently characterized, particularly in heterogeneous populations. Genetically isolated populations offer an effective strategy to overcome these limitations. Finland, shaped by historical demographic events, harbors a distinctive spectrum of enriched rare variants that can facilitate gene discovery. The FinnGen initiative capitalizes on this setting by combining extensive genotyping with nationwide health registry data through a coordinated network of Finnish biobanks. With half a million participants analyzed, FinnGen supports highly powered analyses across a broad array of clinical outcomes and registry data. Recent comprehensive analyses have reported thousands of significant genotype-phenotype associations, including novel protein‑altering variants. Importantly, the FinnGen cohort structure favors older individuals and hospital‑derived samples, increasing representation of brain disorders, such as AD and idiopathic normal pressure hydrocephalus (iNPH), a disorder frequently accompanied by AD‑like pathological features. In this expert review, we summarize FinnGen‑based investigations relevant to neurodegenerative diseases and iNPH, highlighting insights into genetic susceptibility, disease overlap, and protective factors, and discuss how integration with recall studies as well as biomarker and clinical data accelerates translational applications in brain disorders.