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Genetic variants influencing human aging from late-onset Alzheimer’s disease (LOAD) genome-wide association studies (GWAS)

Hui Shia, Olivia Belbina, Christopher Medwaya, Kristelle Browna, Noor Kalshekera, Minerva Carrasquillob, Petroula Proitsic, John Powellc, Simon Lovestonec, Alison Goated, Steven Younkinb, Peter Passmoree, the Genetic and Environmental Risk for Alzheimer’s Disease (GERAD1) Consortium1, Kevin Morgana,*, for the Alzheimer’s Research UK

Received 12 September 2011; received in revised form 16 January 2012; accepted 11 February 2012

Abstract

Genetics plays a crucial role in human aging with up to 30% of those living to the mid-80s being determined by genetic variation. Survival to older ages likely entails an even greater genetic contribution. There is increasing evidence that genes implicated in age-related diseases, such as cancer and neuronal disease, play a role in affecting human life span. We have selected the 10 most promising late-onset Alzheimer’s disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1) have been tested for association with human aging in our dataset (1385 samples with documented age at death [AAD], age range: 58–108 years; mean age at death: 80.2) using the most significant single nucleotide polymorphisms (SNPs) found in the previous studies. Apart from the APOE locus (rs2075650) which showed compelling evidence of association with risk on human life span (p p=! 5.27 1X | 10(cid:3)4), none of the other LOAD gene loci demonstrated significant evidence of association. In addition to examining the known LOAD genes, we carried out analyses using age at death as a quantitative trait. No genome-wide significant SNPs were discovered. Increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in the future. In this report, we also discuss issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome-wide significant signals from real SNP associations.

Keywords: Lifespan; Late onset Alzheimer’s disease; GWAS; Aging; Genes

* Corresponding author at: University of Nottingham, Human Genetics, School of Molecular Medical Science, Queen’s Medical Centre, Nottingham NG7 2UH, United Kingdom. Tel.: (cid:4)44 0115 8230724.

1 Data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer’s Disease (GERAD1) Consortium. As such, the investigators within the GERAD1 consortia contributed to the design and implementation of GERAD1 and/or provided data but did not participate in analysis or writing of this report. A full list of GERAD1 investigators can be found in the Acknowledgement section.

2 The Alzheimer’s Research UK Consortium: Peter Passmore, David Craig, Janet Johnston, Bernadette McGuinness, Stephen Todd, Queen’s University Belfast, UK; Reinhard Heun (now at Royal Derby Hospital), Heike Kölsch, University of Bonn, Germany; Patrick G. Kehoe, University of Bristol, UK; Nigel M. Hooper, Emma R.L.C. Vardy (now at University of Newcastle), University of Leeds, UK; David M. Mann, University of Manchester, UK; Kristelle Brown, Noor Kalsheker, Kevin Morgan, University of Nottingham, UK; A. David Smith, Gordon Wilcock, Donald Warden, University of Oxford (OPTIMA), UK, Clive Holmes, University of Southampton, UK.

0197-4580/$ – see front matter © 2012 Elsevier Inc. All rights reserved. 10.1016/j.neurobiolaging.2012.02.014

1. Introduction

al., 2003; Kenyon, 2010;). Genetic inactivation of the daf-2 gene (encoding the IGF-1 receptor homolog in C. elegans) increases the lifespan of C. elegans by approximately 100% (Sebastiani et al., 2009). Interestingly, there is emerging evidence that genes such as IGF-1/IGF1R (the orthologs of which play a major part in aging in animals) can play a role in human life span. Loss of function mutations in IGF1R have been found to be overrepresented in Ashkenazi Jewish centenarians compared with controls (Suh et al., 2008).

Human aging is affected by both environmental and genetic factors (Cutler and Mattson, 2006). The heritability of aging is estimated to be 20%–30% to reach mid-80s estimated from twin studies. Survival to older ages likely involves an even greater genetic contribution (Herskind et al., 1996; Iachine et al., 1998; McGue et al., 1993). Fur- thermore, previous studies have shown that siblings of cen- tenarians have an approximately 4-fold higher chance of survival to their early 90s compared with siblings of indi- viduals who die at 73 years of age (Perls et al., 1998). A larger study conducted by the same group has shown an even higher increase (8–18-fold) in the “risk” of successful aging for siblings of centenarians compared with random controls (US 1900 birth cohort) (Perls et al., 2002). Evi- dence indicates strong familial aggregation toward aging.

Aging genes in humans may not only increase the span but also postpone age-related diseases. A study has indicated a significant decreased prevalence age related diseases in offspring of long-lived parents pertension by 23%, diabetes mellitus by 50%, heart by 60%, and no incidences of stroke) compared with age-matched control groups (Atzmon et al., 2004).

The molecular genetics that underlie the human aging process is complex and it is suggested that successful aging is likely due to numerous genes and environmental factors, each exerting a small effect (Kenyon, 2010; Lescai et al., 2009; Plomin et al., 2009).