Hyun-Sik Yang, United States of America

Brigham and Women's Hospital Neurology
Dr. Hyun-Sik Yang is an Assistant Professor of Neurology at Harvard Medical School, and an Associate Neurologist at Brigham and Women’s Hospital’s Division of Cognitive and Behavioral Neurology. Dr. Yang is a physician scientist working at the Center for Alzheimer Research and Treatment (CART) at Brigham and Women’s Hospital and Massachusetts General Hospital. Dr. Yang graduated from Seoul National University College of Medicine (2009) and finished his residency at the Harvard Neurology Residency Program at Brigham and Women’s Hospital and Massachusetts General Hospital (2016). He finished his behavioral neurology and neuropsychiatry fellowship at Brigham and Women’s Hospital (2018). Dr. Yang’s research focuses on elucidating mechanistic relations among multiple causes of dementia using functional genomics, biomarkers, and post-mortem neuropathology.

Presenter of 2 Presentations

 Conference Calendar

LIVE DISCUSSION

Session Name
LIVE DISCUSSION - TDP-43 IN ALS AND FTD
Session Type
LIVE SYMPOSIUM DISCUSSION
Date
11.03.2021, Thursday
Session Time
16:30 - 17:00
Room
Live Symposia Discussion C
Lecture Time
16:30 - 17:00
Presenter
Session Icon
Live

GENOME-WIDE ASSOCIATION STUDY IMPLICATES APOE, GRM8, AND TYPE I INTERFERON PATHWAY IN LIMBIC-PREDOMINANT AGE-RELATED TDP-43 ENCEPHALOPATHY PATHOGENESIS

Session Name
TDP-43 IN ALS AND FTD
Session Type
SYMPOSIUM
Date
11.03.2021, Thursday
Session Time
10:00 - 11:45
Room
On Demand Symposia C
Lecture Time
10:30 - 10:45
Presenter
Session Icon
On-Demand

Abstract

Aims

To elucidate the genetic architecture of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), a common TDP-43 proteinopathy that is frequently comorbid with Alzheimer’s disease (AD) and increases dementia risk.

Methods

We studied the Religious Orders Study and the Rush Memory and Aging Project participants of European ancestry with imputed genotypes and post-mortem TDP-43 immunohistochemistry (n=1,180). TDP-43, amyloid-β (Aβ), and paired helical filament tau (PHFtau) were quantified using immunohistochemistry. LATE-NC burden was defined as a semi-quantitative six-point scale of TDP-43 burden averaged across six brain regions including amygdala, hippocampus, and neocortex. Genome-wide association study (GWAS) was performed using linear additive models controlling for age, sex, genotyping platform, and first three principal components from the genotype covariance matrix.

Results

Two distinct loci reached genome-wide significance in their association with higher LATE-NC burden: rs429358C, an allele defining the APOE ε4 haplotype (beta=0.46, p=1.2×10-12); rs17608393A within GRM8 (beta=0.68, p=4.5×10-8). There were 10 additional loci that reached pre-defined suggestive significance (p<10-6). A suggestive variant rs72701368G (beta=0.54, p=1.1×10-7) tagged a large haplotype spanning the interferon-alpha (IFNA) gene cluster, and another suggestive variant rs56902449A (beta=0.72, p=8.0×10-7) was a cis-eQTL increasing the expression of MX2, a gene encoding interferon-induced GTP-binding protein Mx2. After adjusting for Aβ and PHFtau, the association between APOE rs429358C and LATE-NC was partially attenuated (beta=0.28, p=2.6×10-5), while GRM8 and IFNA variants’ association with LATE-NC remained similar.latenc_gwas_fig1_09172020.jpg

Conclusions

AD-related APOE locus and AD-independent GRM8 locus were associated with LATE-NC burden, and converging evidence also implicated type I interferon pathway that is regulated by TBK1 (a FTD/ALS risk gene).

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