The aims of SEGWAY study are the following:
Aim 1: Explore genetic determinants for MRI-markers of brain structure in young adults
1a: Explore the heritability of MRI-defined structural brain phenotypes in young adults in their early twenties.
1b: Examine whether genetic loci associated with structural brain phenotypes in older persons, and with dementia, are already associated with structural brain alterations in young adults.
1c: Performing a “hypothesis-free” search for genetic variants associated with structural brain phenotypes in young adults using a genome-wide agnostic approach.
Aim 2: Explore the shared genetic basis of structural brain changes in young and older adults, and the modifying effect of vascular risk factors.
2a: Examine shared genetic risk variants for structural brain phenotypes in young and older adults using a novel
approach based on single-nucleotide polymorphism-derived genomic relationships.
2b: Test if variants yielding the most significant associations with markers of brain structure in young adults are also associated with MRI-markers of structural brain aging in older community persons.
2c: Explore the potential modifying effect of vascular risk factors with an established impact on structural brain aging on genetic associations with structural brain phenotypes, using innovative statistical approaches.
Aim 3: Examine the clinical and functional significance of loci associated with structural brain phenotypes across the lifespan
3a: Test for association of risk variants for structural brain phenotypes with cognitive performance at both ends of the age spectrum.
3b: Perform whole genome sequencing (WGS), with 30X or more coverage, of 600 i-Share participants to better dissect the genetic variants contributing to these associations a comprehensive assessment of all coding and noncoding variants, both common and rare.
3c: Perform in silico annotation (using cutting-edge bioinformatics tools) of the most significant genetic variants, to explore the functional significance of these variants, such as their impact on gene expression.