Genetic report abstractContribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls
Introduction
In Alzheimer's disease (AD), a substantial genetic component has been reported with heritability ranging from 58% to 79% (Gatz et al., 2006), and the advent of the genomic high throughput approaches has allowed deciphering a part of this genetic landscape. In particular, genome-wide association studies (GWAS) led to the discovery of more than 25 loci in which frequent variants are associated with AD risk (Harold et al., 2009, Hollingworth et al., 2011, Jun et al., 2016, Lambert et al., 2013a, Lambert et al., 2013b, Lambert et al., 2009, Naj et al., 2011, Seshadri et al., 2010), some of them confirming previous candidate-gene results (e.g., SORL1 (Rogaeva et al., 2007)).
However, although our knowledge of the genetics of AD has progressed markedly over the last few years, it is still far from complete and as with other multifactorial diseases, deciphering the “missing heritability” is one of the main challenges. It has been suggested that rare variants, not captured by classical GWAS approaches, might explain a part of the missing heritability. With the development and generalization of whole-exome sequencing (WES) and whole-genome sequencing (WGS) approaches, it is now possible to assess such a hypothesis. In the AD field, exome-wide significant association of rare variants in TREM2, SORL1, and ABCA7 with AD risk has been reported (Guerreiro et al., 2013, Jonsson et al., 2013, Nicolas et al., 2016a, Steinberg et al., 2015). However, these seminal analyses have often been performed in populations of restricted size or with a limited panel of variants, restricting the possibility to fully estimate how these rare variant groups explain the susceptibility to AD and how they may influence a disease as heterogeneous as AD. Indeed, one can argue that, in particular, they may affect age at onset which can spread out over several decades from early 40s to very old age. In addition, as there are several types of rare variants, each leading to different biological consequences, deciphering for each gene whether they act through a loss or gain of function is of particular interest for establishing their pathophysiological mechanisms.
To assess these points, we took advantage of the Alzheimer Disease Exome Sequencing-France (ADES-FR) data set, one of the largest AD WES data set available worldwide and made up of 1779 AD cases and 1273 controls, all originating from France. We focused on the TREM2, SORL1, and ABCA7 genes but also included in this study 3 other genes, namely PLD3 (Cruchaga et al., 2014), AKAP9 (Logue et al., 2014), and UNC5C (Wetzel-Smith et al., 2014), which the association of rare variants with AD risk has recently been reported, albeit with lesser evidence. PLD3 association reached exome-wide significance in the first study (Cruchaga et al., 2014), but this result was challenged by 4 different subsequent reports (Heilmann et al., 2015, Hooli et al., 2015, Lambert et al., 2015, van der Lee et al., 2015), and regarding AKAP9 and UNC5C, the exome-wide threshold was not reached.
Section snippets
ADES-FR samples
The ADES-FR project combines WES and WGS data from AD cases and controls (Supplementary Table 1).
Lille cases were selected from the European Alzheimer's Disease Initiative (EADI) data set (Lambert et al., 2009). Clinical diagnosis of AD was established by neurologists according to the DSM-III-R and NINCDS-ADRDA criteria (McKhann et al., 1984).
Patient ascertainment of the Rouen cases is described in detail in Nicolas et al., 2016a, Nicolas et al., 2016b. Briefly, unrelated cases with early-onset
Results
We gathered evidence for gene-based association of rare variants with AD in 6 genes (Table 2 and Supplementary Tables 2 and 3). All variants included in this analysis were observed at the heterozygous state, except the TREM2 p.R47H variant, for which one individual is homozygous. Exome-wide significance was achieved for TREM2 (OR = 6.30 [2.86–13.86], p = 2.28 × 10−7), SORL1 (OR = 3.41 [2.09–5.55], p = 1.61 × 10−7), and ABCA7 (OR = 2.54 [1.72–3.76], p = 9.33 × 10−7) on PTVs+SD variants in EOAD
Discussion
In this study focusing on 6 genes, exome-wide significant association between EOAD risk and specific classes of rare variants was reached for 3 genes: TREM2, SORL1, and ABCA7. Patients and controls were carefully matched for ethnic origin. The inclusion of 236 controls with age below 65 years may at most reduce the power to detect a risk factor.
Our findings on TREM2 indicate that the association signal is due to a collection of rare PTVs+SD variants and is robust to the exclusion of the
Conclusions
Our study confirms previous gene-level results for TREM2, SORL1, and ABCA7. We observe that despite differential strengths of association and varying cumulative MAFs, TREM2, SORL1, and ABCA7 PTVs+SD variants eventually contribute similarly to the genetic component of EOAD at the level of about 1%–1.5% of EOAD heritability each, to be compared with the 9.12% of EOAD heritability attributable to APOE ε4. Obviously, these cumulative contributions depend on our definition of PTVs+SD variants.
Disclosure statement
The authors declare that they have no competing interests.
Acknowledgements
The authors are indebted to the Banque d'ADN et de cellules-Institut du Cerveau et de la Moelle épinière (ICM-Inserm U1127-UPMC P6 UMR S 1127-CNRS UMR 7225), Alzheimer's association (BFG-14-318355) and Agence Nationale pour la Recherche (ANR-15-CE16-0002). All subjects enrolled in this study gave a signed consent. This study was approved by the Paris Necker Ethic Committee.
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