To help to analyze and understand aging-related """"""""complex"""""""" traits that are affected by many genes and environmental factors, we propose to develop three statistical algorithms for the analyses of genome-wide genotyping and high-throughput sequencing studies. To test these algorithms, we take advantage of the special features of the SardiNIA project (see Z01 AG000675-06), which has collected longitudinal data for >300 quantitative traits together with the whole-genome genetic data in the founder Sardinia population. To analyze mitochondrial DNA variation and its possible effects on aging-related traits, the genotype-calling and analytic programs developed for nuclear DNA are not adequate, because each cell has 100-10,000 mtDNA copies that can vary at any site (heteroplasmy), and can therefore have each of the 4 bases at any position in various copies. We have developed an algorithm that is specific to identify variants in mtDNA;it incorporates the sequencing error rate at each base in each sequence read and has the flexibility to allow for different allele fractions at a variant site across all individuals. It has thus far been successful in assessing homoplasmies in the mtDNA sequence from 1,000 sequenced individuals. Especially because the Sardinian cohort is highly inter-related, we have also been able to distinguish newly-arising variants in children compared to their mothers and other relatives. To take advantage of repeated visits, which can increase the accuracy of data and thereby provide more highly significant results with a given size sample, we have, instead of using the average of multiple measurements, developed an empirical Bayes shrinking estimator that uses weighted estimates from all measurements. Simulations and analysis of real data from the SardiNIA data set show that combining values from repeated visits in an association study yields an increase in GWAS signals compared to using a single visit for measures of many traits at 3 visits over a 10-year period. Furthermore, we have showed that in unbalanced data sets (that is, with different individuals having different numbers of visits), the shrinking estimator further improves GWAS signals relative to the average. This work has been accepted for publication in the European Journal of Human Genetics. To take advantage of correlations between related traits and hence to increase statistical power for genetic studies, in ongoing work, we are developing a method to search for genes/variants that have pleiotropic effects on multiple quantitative traits.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Institute on Aging
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Qian, Yong; Butler, Thomas J; Opsahl-Ong, Krista et al. (2017) fastMitoCalc: an ultra-fast program to estimate mitochondrial DNA copy number from whole-genome sequences. Bioinformatics 33:1399-1401
Okbay, Aysu (see original citation for additional authors) (2016) Genome-wide association study identifies 74 loci associated with educational attainment. Nature 533:539-42
van den Berg, St├ęphanie M; de Moor, Marleen H M; Verweij, Karin J H et al. (2016) Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium. Behav Genet 46:170-82
Okbay, Aysu; Baselmans, Bart M L; De Neve, Jan-Emmanuel et al. (2016) Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nat Genet 48:624-33
Ding, Jun; Sidore, Carlo; Butler, Thomas J et al. (2015) Assessing Mitochondrial DNA Variation and Copy Number in Lymphocytes of ~2,000 Sardinians Using Tailored Sequencing Analysis Tools. PLoS Genet 11:e1005306
Terracciano, Antonio; Strait, James; Scuteri, Angelo et al. (2014) Personality traits and circadian blood pressure patterns: a 7-year prospective study. Psychosom Med 76:237-43
Pelosi, Emanuele; Omari, Shakib; Michel, Marc et al. (2013) Constitutively active Foxo3 in oocytes preserves ovarian reserve in mice. Nat Commun 4:1843
Hek, Karin; Demirkan, Ayse; Lahti, Jari et al. (2013) A genome-wide association study of depressive symptoms. Biol Psychiatry 73:667-78
Meirelles, Osorio D; Ding, Jun; Tanaka, Toshiko et al. (2013) SHAVE: shrinkage estimator measured for multiple visits increases power in GWAS of quantitative traits. Eur J Hum Genet 21:673-9
Voight, Benjamin F; Kang, Hyun Min; Ding, Jun et al. (2012) The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet 8:e1002793

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