Differential burden of rare protein truncating variants in Alzheimer's disease patients compared to centenarians

T2D-GENES Consortium

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3096-3105
Number of pages10
JournalHuman Molecular Genetics
Volume25
Issue number14
DOIs
StatePublished - 2016

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Alzheimer Disease
Initiator Codon
Proteins
Genome
Exome
Gene Frequency
Sample Size
Genes
Databases
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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Differential burden of rare protein truncating variants in Alzheimer's disease patients compared to centenarians. / T2D-GENES Consortium.

In: Human Molecular Genetics, Vol. 25, No. 14, 2016, p. 3096-3105.

Research output: Contribution to journalArticle

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abstract = "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.",
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T1 - Differential burden of rare protein truncating variants in Alzheimer's disease patients compared to centenarians

AU - T2D-GENES Consortium

AU - Freudenberg-Hua, Yun

AU - Li, Wentian

AU - Abhyankar, Avinash

AU - Vacic, Vladimir

AU - Cortes, Vanessa

AU - Ben-Avraham, Danny

AU - Koppel, Jeremy

AU - Greenwald, Blaine

AU - Germer, Soren

AU - Darnell, Robert B.

AU - Barzilai, Nir

AU - Freudenberg, Jan

AU - Atzmon, Gil

AU - Davies, Peter

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