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Genetic architecture of hematologic traits and healthy aging-related endophenotypes in the long life family study

Singh, Jatinder (2014) Genetic architecture of hematologic traits and healthy aging-related endophenotypes in the long life family study. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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One of the goals of medicine and public health is to increase functional longevity. Anemia and other age-related blood cell trait abnormalities have been shown to be associated with adverse outcomes such as disability, hospitalization, morbidity and mortality in older adults. Results from the third National Health and Nutrition Survey (1988-1994) indicated that 11.0% of men and 10.2% of women ≥ 65 years of age were anemic. As the US and global populations age, the prevalence of hematologic disorders and all age-related disorders will increase. The identification of genes or novel biological pathways that regulate hematologic traits and healthy-aging phenotypes could lead to insights and possible future interventions to delay the onset of hematologic diseases, increase functional longevity, and concomitantly, decrease the burden of age-related diseases on public health. In the current study, data on from a unique population comprising long-lived siblings and their families (the Long Life Family Study) were used to identify genes that may influence age-related traits, such hematologic traits and healthy aging endophenotypes. Using family-based whole genome linkage and association analyses, I identified multiple loci that may affect hematologic traits and endophenotypes. The most promising results are as follows. I identified (and subsequently replicated) a locus on chromosome 11p15.2 near SOX6 (a transcription factor gene) that influenced RBC count. I also used factor analyses to extend results of previously developed endophenotypes derived from five health domains (cognition, physical function, cardiovascular, metabolic and pulmonary). The primary endophenotype (predominantly reflecting pulmonary and physical function traits) was significantly related to reduced mortality. In addition, this endophenotype and the relationship to mortality was replicated in an independent, population-based cohort. I also identified (and replicated) association of this endophenotype to a locus on chromosome 18q11.2 near ZNF521, a transcription factor gene. Intriguingly, both SOX6 and ZNF521 have been reported to play a role in erythropoiesis, consistent with the hypothesis that aging may result, in part, from fundamental biological processes that influence multiple disorders. These results also indicate that genetic studies in a unique set of families may reveal novel findings that will increase our understanding of the genetic regulation of aging.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Singh, Jatinderjas285@pitt.eduJAS285
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberBarmada, Michaelbarmada@pitt.eduBARMADA
Committee MemberWeeks, Danielweeks@pitt.eduWEEKS0000-0001-9410-7228
Committee MemberNewman, AnneNewmanA@edc.pitt.eduANEWMAN
Committee ChairKammerer, Candacecmk3@pitt.eduCMK3
Date: 27 June 2014
Date Type: Publication
Defense Date: 17 December 2013
Approval Date: 27 June 2014
Submission Date: 7 April 2014
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 187
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: healthy aging; longevity; hematologic traits; blood; red blood cells; heritability; genome-wide linkage analysis; genome-wide association analysis
Date Deposited: 27 Jun 2014 20:29
Last Modified: 30 Jun 2022 16:17


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