Differential burden of rare protein truncating variants in Alzheimer's disease patients compared to centenarians.
We compared coding region variants of 53 cognitively healthy centenarians and 45 patients with Alzheimer's disease (AD), all of Ashkenazi Jewish (AJ) ancestry. Despite the small sample size, the known AD risk variant APOE4 reached genome-wide significance, indicating the advantage of utilizing 'super-controls'. We restricted our subsequent analysis to rare variants observed at most once in the 1000 Genomes database and having a minor allele frequency below 2% in our AJ sample. We compared the burden of predicted protein altering variants between cases and controls as normalized by the level of rare synonymous variants. We observed an increased burden among AD subjects for predicted loss-of-function (LoFs) variants defined as stop-gain, frame shift, initiation codon (INIT) and splice site mutations (n = 930, OR = 1.3, P = 1.5×E-5). There was no enrichment across all rare protein altering variants defined as missense plus LoFs, in frame indels and stop-loss variants (n = 13 014, OR = 0.97, P = 0.47). Among LoFs, the strongest burden was observed for INIT (OR = 2.16, P = 0.0097) and premature stop variants predicted to cause non-sense-mediated decay in the majority of transcripts (NMD) (OR = 1.98, P = 0.02). Notably, this increased burden of NMD, INIT and splice variants was more pronounced in a set of 1397 innate immune genes (OR = 4.55, P = 0.0043). Further comparison to additional exomes indicates that the difference in LoF burden originated both from the AD and centenarian sample. In summary, we observed an overall increased burden of rare LoFs in AD subjects as compared to centenarians, and this enrichment is more pronounced for innate immune genes.
Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030, USA yfreuden@northwell.edu.|Division of Geriatric Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY 11004, USA.
Yun
Y
Freudenberg-Hua
Robert S Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030, USA.
Wentian
W
Li
New York Genome Center, New York, NY 10013, USA.
Avinash
A
Abhyankar
New York Genome Center, New York, NY 10013, USA.
Vladimir
V
Vacic
Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030, USA.
Vanessa
V
Cortes
Institute for Aging Research and the Diabetes Research Center, Department of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Danny
D
Ben-Avraham
Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030, USA.
Jeremy
J
Koppel
Division of Geriatric Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY 11004, USA.
Blaine
B
Greenwald
New York Genome Center, New York, NY 10013, USA.
Soren
S
Germer
New York Genome Center, New York, NY 10013, USA.
Robert B
RB
Darnell
Institute for Aging Research and the Diabetes Research Center, Department of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Nir
N
Barzilai
Robert S Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030, USA.|The Regeneron Genetics Center, Tarrytown, NY 10591, USA and.
Jan
J
Freudenberg
Institute for Aging Research and the Diabetes Research Center, Department of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.|Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel.
Gil
G
Atzmon
Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030, USA.
Peter
P
Davies
D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D053327:Apolipoprotein E4 / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D054643:INDEL Mutation; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D007585:Jews / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide
D053327:Apolipoprotein E4