Linkage and association of successful aging to the 6q25 region in large Amish kindreds

Received: 9 December 2011 /Accepted: 11 June 2012 /Published online: 7 July 2012 # American Aging Association 2012

Abstract Successful aging (SA) is a multidimension- al phenotype involving living to older age with high physical function, preserved cognition, and continued social engagement. Several domains underlying SA are heritable, and identifying health-promoting poly- morphisms and their interactions with the environment could provide important information regarding the health of older adults. In the present study, we exam- ined 263 cognitively intact Amish individuals age 80 “ ” and older (74 SA and 189 normally aged ) all of

whom are part of a single 13-generation pedigree. A genome-wide association study of 630,309 autosomal single nucleotide polymorphisms (SNPs) was per- formed and analyzed for linkage using multipoint analyses and for association using the modified quasi-likelihood score test. There was evidence for linkage on 6q25-27 near the fragile site FRA6E region with a dominant model maximum multipoint hetero- 0 geneity LOD score 3.2. The 1-LOD-down support interval for this linkage contained one SNP for which

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D. R. V. Edwards J. R. Gilbert J. E. Hicks J. L. Myers : : : : S. Guo P. J. Gallins I. Konidari L. Caywood : : L. Reinhart-Mercer M. A. Pericak-Vance W. K. Scott (*) Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute of Human Genomics, Miller School of Medicine, University of Miami,

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, USA

Present Address:

Center for Human Genetics Research, Vanderbilt University Epidemiology Center, Institute of Medicine and Public Health, Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, TN, USA

there was regionally significant evidence of association (rs205990, p0 2.36×10−5). This marker survived interval-wide Bonferroni correction for multiple testing and was located between the genes QKI and PDE10A. Other areas of chromosome 6q25- q27 (including the FRA6E region) contained sev- 0 eral SNPs associated with SA (minimum p 2.89× 10−6). These findings suggest potentially novel genes in the 6q25-q27 region linked and associat- ed with SA in the Amish; however, these findings should be verified in an independent replication cohort.

Previous genetic studies of SA have focused on three primary categories of genes selected primarily for their relevance to aging-associated pathophysio- logical processes or processes that are known to change during the aging process (Glatt et al. 2007). These categories include: (1) genes involved in the maintenance of cholesterol, lipid, and/or lipoproteins (Arking et al. 2005; Cellini et al. 2005; Taioli et al. 2001); (2) genes that influence inflammation and im- mune response, particularly cytokines, many of which also influence cell cycling, growing, motility, and signaling (Capurso et al. 2004; Naumova et al. 2004); and (3) genes involved in drug metabolism (Taioli et al. 2001). To date, few of the candidate genes associated with SA have been successfully replicated, with the exception of a few studies that have associated with longevity but not SA (Atzmon et al. 2009a; Banasik et al. 2011; Chung et al. 2010; Deelen et al. 2011; Kleindorp et al. 2011; Li et al. 2009; Nebel et al. 2011; Snejdrlova et al. 2011), suggesting that this approach may not be the best for a complex trait such as SA.

Introduction

With the rapid expansion of the population over age 60, understanding the components of successful aging (SA) is becoming a critical component of the medical and public health response to this demographic shift. The number of adults over age 60 is predicted to reach two billion worldwide by the year 2050, more than doubling from 2000 (US Census Bureau Population Division and Housing and Household Economic Sta- tistics Division 2001). This growing elderly popula- tion could dramatically impact our health care system depending on how successfully this population ages with regard to multiple factors such as physical, men- tal, and social well-being. Surprisingly, a large propor- tion of older adults has continued to function at a high “ ” level and has aged successfully (Depp and Jeste 2006). Understanding why some individuals avoid significant decline in physical function and suscepti- bility to age-related diseases might help guide clinical care and provide the basis for novel programs to prevent or slow such declines.

Genome-wide association studies (GWAS) avoid choosing specific candidate genes in favor of broadly surveying common variation across the entire genome. Two GWAS for extreme longevity (living past age 90 (Newman et al. 2010) and living past age 100) have recently been published, and three other GWAS, one for healthy cognitive aging past age 85 (Poduslo et al. 2009), one for disease-free survival after age 65 (Lunetta et al. 2007), and one for survival of 89 years for men and 91 years for women (Deelen et al. 2011) have also been published. There is significant variabil- ity across studies with regard to how longevity is defined as surviving beyond a certain age and others are based on being healthy and disease free up to a certain age. This inconsistency in the definition has made it difficult to compare findings across studies. To our knowledge, a GWAS has not been performed for a dichotomous successful aging outcome defined as maintaining function in cognition, physical function, and social engagement at age 80 or older. In this report, we present a genome-wide linkage and associ- ation study examining 74 successfully aged and 189 “ ” normally aged Amish adults over age 80 living in several communities in Indiana and Ohio. Genetic