Genetic analysis of quantitative phenotypes in AD and MCI: imaging, cognition and biomarkers

Abstract

The Genetics Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI), formally established in 2009, aims to provide resources and facilitate research related to genetic predictors of multidimensional Alzheimer's disease (AD)-related phenotypes. Here, we provide a systematic review of genetic studies published between 2009 and 2012 where either ADNI APOE genotype or genome-wide association study (GWAS) data were used. We review and synthesize ADNI genetic associations with disease status or quantitative disease endophenotypes including structural and functional neuroimaging, fluid biomarker assays, and cognitive performance. We also discuss the diverse analytical strategies used in these studies, including univariate and multivariate analysis, meta-analysis, pathway analysis, and interaction and network analysis. Finally, we perform pathway and network enrichment analyses of these ADNI genetic associations to highlight key mechanisms that may drive disease onset and trajectory. Major ADNI findings included all the top 10 AD genes and several of these (e.g., APOE, BIN1, CLU, CR1, and PICALM) were corroborated by ADNI imaging, fluid and cognitive phenotypes. ADNI imaging genetics studies discovered novel findings (e.g., FRMD6) that were later replicated on different data sets. Several other genes (e.g., APOC1, FTO, GRIN2B, MAGI2, and TOMM40) were associated with multiple ADNI phenotypes, warranting further investigation on other data sets. The broad availability and wide scope of ADNI genetic and phenotypic data has advanced our understanding of the genetic basis of AD and has nominated novel targets for future studies employing next-generation sequencing and convergent multi-omics approaches, and for clinical drug and biomarker development.

Fig. 1

Distribution of publications using the ADNI APOE and GWAS genotyping data between 2009 and 2012: Of the 106 papers, 30 papers used only APOE data, and 76 papers used GWAS data

Fig. 2

As reported in (Saykin et al. 2012), FRMD6 (FERM domain-containing protein 6) was detected in 3 imaging genetics studies using the ADNI data (Potkin et al. ; Stein et al. ; Furney et al. 2011) and validated by case control GWAS (Hong et al. 2012)

Fig. 3

Comparison of sample sizes to reach a GWAS significance level of p < 10⁻⁸ for case controls and QT approaches for a p < 10⁻⁸ (OR = 1.5) with 10 % variance explained for the QT, a MAF of .10 and marker SNP MAF = .20. (See also Potkin et al. 2009e)

Fig. 4

Multi-level brain-genome association strategies and examples of studies in each category (Risacher et al. ; Sloan et al. ; Potkin et al. ; Saykin et al. ; Risacher et al. ; Swaminathan et al. ; Potkin et al. ; Ho et al. ; Reiman et al. ; Chiang et al. ; Shen et al. ; Stein et al. 2010a). Relevant thumbnails were reprinted by permissions from (1) Elsevier: [Neurobiology of Aging], (Risacher et al. 2010), copyright (2010); (2) John Wiley & Sons, Inc.: [American Journal of Medical Genetics], (Sloan et al. 2010), copyright (2010); (3) Elsevier: [Alzheimer's & Dementia], (Saykin et al. 2010), copyright (2010); (4) the terms of the Creative Commons Attribution Non Commercial License: [Frontiers in Aging Neuroscience], (Risacher et al. 2013), copyright (2013); (5) Macmillan Publishers Ltd: [Molecular Psychiatry], (Potkin et al. 2009c), copyright (2009); (6) the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License: [Journal of Neuroscience], (Chiang et al. 2012), copyright (2012); and (7) Elsevier: [Neuroimage], (Shen et al. 2010), copyright (2010)

Fig. 5

Chilibot analysis on 51 genes discovered from ADNI structural MRI genetic studies. Chilibot (http://www.chilibot.net/) searches PubMed abstracts and constructs content-rich relationship networks among biological concepts, genes, proteins, or drugs. We did a Chilibot query using 51 genes discovered from ADNI structural MRI genetic studies. No relationship was reported for five genes: BICD1, CAND1, GPCPD1, MAD2L2, and PRUNE2. We further filtered the graph by displaying only interactive relationships (i.e., excluding non-interactive relationship and abstract co-occurrence only). Shown here is the resulting graph, containing 51 − 5 = 46 query terms. Note that the 15 isolated genes shown in the bottom were included in the figure, due to the existence of non-interactive relationship or abstract co-occurrence only relationship (not shown) between them and some query genes. They were shown here as isolated units because there was no interactive relationship connecting them to other genes