Integration of bioinformatics and imaging informatics for identifying rare PSEN1 variants in Alzheimer's disease

Kwangsik Nho, Emrin Horgusluoglu, Sungeun Kim, Shannon L. Risacher, Dokyoon Kim, Tatiana Foroud, Paul S. Aisen, Ronald C. Petersen, Clifford R. Jack, Leslie M. Shaw, John Q. Trojanowski, Michael W. Weiner, Robert C. Green, Arthur W. Toga, Andrew J. Saykin

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Background: Pathogenic mutations in PSEN1 are known to cause familial early-onset Alzheimer's disease (EOAD) but common variants in PSEN1 have not been found to strongly influence late-onset AD (LOAD). The association of rare variants in PSEN1 with LOAD-related endophenotypes has received little attention. In this study, we performed a rare variant association analysis of PSEN1 with quantitative biomarkers of LOAD using whole genome sequencing (WGS) by integrating bioinformatics and imaging informatics. Methods: A WGS data set (N = 815) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort was used in this analysis. 757 non-Hispanic Caucasian participants underwent WGS from a blood sample and high resolution T1-weighted structural MRI at baseline. An automated MRI analysis technique (FreeSurfer) was used to measure cortical thickness and volume of neuroanatomical structures. We assessed imaging and cerebrospinal fluid (CSF) biomarkers as LOAD-related quantitative endophenotypes. Single variant analyses were performed using PLINK and gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). Results: A total of 839 rare variants (MAF < 1/ (2 N) = 0.0257) were found within a region of ±10 kb from PSEN1. Among them, six exonic (three non-synonymous) variants were observed. A single variant association analysis showed that the PSEN1 p. E318G variant increases the risk of LOAD only in participants carrying APOE ϵ4 allele where individuals carrying the minor allele of this PSEN1 risk variant have lower CSF Aβ1-42 and higher CSF tau. A gene-based analysis resulted in a significant association of rare but not common (MAF ≥ 0.0257) PSEN1 variants with bilateral entorhinal cortical thickness. Conclusions: This is the first study to show that PSEN1 rare variants collectively show a significant association with the brain atrophy in regions preferentially affected by LOAD, providing further support for a role of PSEN1 in LOAD. The PSEN1 p. E318G variant increases the risk of LOAD only in APOE ϵ4 carriers. Integrating bioinformatics with imaging informatics for identification of rare variants could help explain the missing heritability in LOAD.

Original languageEnglish (US)
Article number30
JournalBMC medical genomics
StatePublished - Aug 12 2016


  • Gene-based association of rare variants
  • Imaging genetics
  • PSEN1
  • Whole genome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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