Heritability and rare variant contributions to Alzheimer disease in the Midwestern Amish
- 1Case Western Reserve University
Abstract
Structured AbstractO_ST_ABSBackgroundC_ST_ABSThe genetic architecture of Alzheimer disease remains incompletely understood. Founder populations such as the Amish offer a unique opportunity to identify additional genetic variation influencing the disease.
MethodUsing extensive pedigree and genomic data from Midwestern Amish communities, we estimated both pedigree- and SNP- based heritability of AD. In addition, genome-wide association studies and gene-based rare variant tests were performed.
ResultsHeritability estimates suggested that common variants explain much of genetic risk among APOE-{varepsilon}4 carriers, while unexplained heritability remains in non-carriers in the Amish. GWAS confirmed APOE-{varepsilon}4 as the strongest genetic determinant of AD in the Amish. Rare variant analyses identified RIN3 and PILRA as significantly associated with risk of cognitive impairment; suggestive signals including CYP24A1 were also identified.
DiscussionThese findings highlight the contributions of common and rare variants to Alzheimer disease and suggest factors beyond common variants may contribute to disease susceptibility particularly among the APOE-{varepsilon}4 non-carriers.
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BibTeX
@misc{liu2026heritability,
title = {{Heritability and rare variant contributions to Alzheimer disease in the Midwestern Amish}},
author = {Y. Liu and Y. E. Song and W. Wang and A. Lynn and K. Miskimen and S. L. Fuzzell and S. D. Hochstetler and R. A. Laux and D. Miller and P. Miron and L. J. Caywood and J. E. Clouse and S. D. Herinton and P. Wang and A. Gulyayev and D. A. Dorfsman and N. C. Moore and D. Z. Jian and L. R. Main and M. B. Prough and A. F. Zaman and L. D. Adams and P. Whitehead and P. Ogrocki and A. J. Lerner and J. M. Vance and M. L. Cuccaro and W. K. Scott and M. A. Pericak-Vance and J. L. Haines},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.26363309},
url = {https://www.medrxiv.org/content/10.64898/2026.09.17.26363309v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Heritability and rare variant contributions to Alzheimer disease in the Midwestern Amish
AU - Y. Liu
AU - Y. E. Song
AU - W. Wang
AU - A. Lynn
AU - K. Miskimen
AU - S. L. Fuzzell
AU - S. D. Hochstetler
AU - R. A. Laux
AU - D. Miller
AU - P. Miron
AU - L. J. Caywood
AU - J. E. Clouse
AU - S. D. Herinton
AU - P. Wang
AU - A. Gulyayev
AU - D. A. Dorfsman
AU - N. C. Moore
AU - D. Z. Jian
AU - L. R. Main
AU - M. B. Prough
AU - A. F. Zaman
AU - L. D. Adams
AU - P. Whitehead
AU - P. Ogrocki
AU - A. J. Lerner
AU - J. M. Vance
AU - M. L. Cuccaro
AU - W. K. Scott
AU - M. A. Pericak-Vance
AU - J. L. Haines
PY - 2026
DA - 2026/09/17
PB - medRxiv
DO - 10.64898/2026.09.17.26363309
UR - https://www.medrxiv.org/content/10.64898/2026.09.17.26363309v1
AB - Structured AbstractO_ST_ABSBackgroundC_ST_ABSThe genetic architecture of Alzheimer disease remains incompletely understood. Founder populations such as the Amish offer a unique opportunity to identify additional genetic variation influencing the disease. MethodUsing extensive pedigree and genomic data from Midwestern Amish communities, we estimated both pedigree- and SNP- based heritability of AD. In addition, genome-wide association studies and gene-based rare variant tests were performed. ResultsHeritability estimates suggested that common variants explain much of genetic risk among APOE-{varepsilon}4 carriers, while unexplained heritability remains in non-carriers in the Amish. GWAS confirmed APOE-{varepsilon}4 as the strongest genetic determinant of AD in the Amish. Rare variant analyses identified RIN3 and PILRA as significantly associated with risk of cognitive impairment; suggestive signals including CYP24A1 were also identified. DiscussionThese findings highlight the contributions of common and rare variants to Alzheimer disease and suggest factors beyond common variants may contribute to disease susceptibility particularly among the APOE-{varepsilon}4 non-carriers.
ER -