Medical College of Wisconsin
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Neuroimaging endophenotypes reveal underlying mechanisms and genetic factors contributing to progression and development of four brain disorders. Nat Biomed Eng 2025 Nov;9(11):1920-1937

Date

06/07/2025

Pubmed ID

40481237

Pubmed Central ID

PMC12955822

DOI

10.1038/s41551-025-01412-w

Scopus ID

2-s2.0-105007361972 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

Recent work leveraging artificial intelligence has offered promise to dissect disease heterogeneity by identifying complex intermediate brain phenotypes, called dimensional neuroimaging endophenotypes (DNEs). We advance the argument that these DNEs capture the degree of expression of respective neuroanatomical patterns measured, offering a dimensional neuroanatomical representation for studying disease heterogeneity and similarities of neurologic and neuropsychiatric diseases. We investigate the presence of nine DNEs derived from independent yet harmonized studies on Alzheimer's disease, autism spectrum disorder, late-life depression and schizophrenia in the UK Biobank study. Phenome-wide associations align with genome-wide associations, revealing 31 genomic loci (P < 5 × 10-8/9) associated with the nine DNEs. The nine DNEs, along with their polygenic risk scores, significantly enhanced the predictive accuracy for 14 systemic disease categories, particularly for conditions related to mental health and the central nervous system, as well as mortality outcomes. These findings underscore the potential of the nine DNEs to capture the expression of disease-related brain phenotypes in individuals of the general population and to relate such measures with genetics, lifestyle factors and chronic diseases.

Author List

Wen J, Skampardoni I, Tian YE, Yang Z, Cui Y, Erus G, Hwang G, Varol E, Boquet-Pujadas A, Chand GB, Nasrallah IM, Satterthwaite TD, Shou H, Shen L, Toga AW, Zalesky A, Davatzikos C

Author

Gyujoon Hwang PhD Assistant Professor in the Psychiatry and Behavioral Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Aged
Alzheimer Disease
Autism Spectrum Disorder
Brain
Brain Diseases
Disease Progression
Endophenotypes
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Middle Aged
Multifactorial Inheritance
Neuroimaging
Phenotype
Schizophrenia