Basic Science and Pathogenesis

Area of Science:

• Neurogenetics
• Environmental Health
• Medical Imaging

Background:

• Epidemiological studies link environmental exposures to Alzheimer's disease and related disorders (ADRD) risk.
• The preclinical phase of ADRD is long, making molecular mechanisms of environmental disruption and brain impact poorly understood.
• Investigating gene-environment interactions is complex due to defining environmental variables and study heterogeneity.

Purpose of the Study:

• To identify genetic loci (variance quantitative trait loci or vQTLs) sensitive to environmental influences on brain structure.
• To investigate how environmental factors mediate gene-environment interactions in preclinical ADRD markers.
• To leverage UK Biobank data for comprehensive analysis of genomic, imaging, and risk factor profiles.

Main Methods:

• Utilized UK Biobank data (N=45,275) to map vQTLs for hippocampal volume (HV), white matter hyperintensity (WMH), and diffusion MRI metrics (FA, MD).
• Employed deviations in phenotypic variance to detect vQTLs with environmental sensitivity.
• Applied linear mixed models to identify environmental exposures mediating vQTL associations.

Main Results:

• Identified five novel genome-wide significant loci for WMH burden and suggestive loci for HV and FA.
• Found that sedentary behavior and lifestyle factors (smoking, alcohol) mediated associations for loci at 2q12.3 (ST6GAL2), 10p11.22 (ZEB1), and 17p11.2 (EPN2) with WMH.
• Discovered ZEB1 regulates gut microbiome species linked to inflammatory bowel diseases, and ST6GAL2 is an inflammatory biomarker associated with alcohol consumption; risk loci were downregulated in the spleen and enriched in kidney cell types.

Conclusions:

• Identified novel genome-wide loci interacting with environmental factors and associated with preclinical MRI markers of Alzheimer's disease.
• Highlighted the significant impact of modifiable lifestyle factors on genetic risk for ADRD.
• Suggested potential preventive and therapeutic strategies based on identified gene-environment interactions and emphasized the need for replication in diverse cohorts.