The SardiNIA study population cohort comprises over 7,000 subjects, starting at ages from 14-102, from a cluster of four towns in Sardinia. The study has been measuring >300 quantitative traits (endophenotypes or quantitative risk-related genetic or environmental factors) that can be scored on a continuous scale, and is designed as a longitudinal studies, with 4 visits over the first 13 years of its tenure. Traits of special interest include a range of cardiovascular risk factors, anthropometric measurements, blood test values, and facets of personality. Fourth visits are now in progress for the study cohort to permit the assessment of longitudinal trends and outcomes, as well as the assessment of additional phenotypes related to bone density and frailty as a function of age. For example, 24 hour blood pressure measurements and ECHOcardiography are extending the analysis of cardiovascular traits;and the cohort is being specifically extended to over 250 individuals over 92 years of age to analyze effects of extreme age. With this cohort, full-genome scans with batteries of single-nucleotide markers were conducted, and were supplemented in the last year with full genome DNA sequencing and genotyping with specialized chips (metabochip, immunochip, and exome chip, and a chip designed to give equal coverage across the entire genome). These have provided a catalogue of over 17,000,000 variants, including a range of relatively rare variants, which are being tested for association with traits and diseases in Genome-wide association scans (GWAS). In addition, 1,000 individuals have provided lymphocyte samples for analysis (see below). In studies thus far, GWAS have pointed to genes/variants that determine a significant portion of the genetic contribution to variance for each trait and disease studied. In conjunction with consortium efforts on other population cohorts, including the Baltimore Longitudinal Study of Aging and the InCHIANTI study supported by the NIA, an increasing number of publications have resulted that identify genes associated with obesity, cardiovascular traits, and levels of lipids and blood components. In particular, genes associated with HbF levels as a modulator of thalassemia/sickle cell disease severity have been identified, as well as findings of genetic factors determining loci for blood pressure, many affecting adiposity;and personality facets affecting under- and over-weight (see bibliography for a complete list). Supporting the range and depth of results are 3 of the most recent publications: in one, human demographic history was reconstructed from DNA sequences of 1,204 Y chromosomes in the cohort;a second inferred DNA variants that control up to 80% of the variability of at least one of 95 separated immune cell types;and a third identified a genetic locus that is associated with part of hereditary capacity for educational attainment. In an additional new initiative in the past year, separation of 95 types of immune system cells was done for 3,400 individuals by flow-sorting to determine levels of general leukocyte sub-populations (B and T, natural killer, monocytes, etc.) and subclasses of T-regulatory cells, dendritic cells, and T cell maturation stages;the variation of levels of many cell types especially Tregs is up to 87% genetically determined;and GWAS analysis on 1,200 individuals with the 12,500,000 SNP set then revealed 23 with a large effect on at least one cell type. For example, the R262W SH2B3 variant, already associated with several autoimmune diseases and negative regulation of hematopoiesis, was shown to particularly affect the numbers of CD4+ T cells, likely resulting in a loss of function. In a complementary approach, cohorts of Sardinian patients and controls were assembled and genotyped for GWAS for each of several diseases, Type 1 diabetes, multiple sclerosis (MS), and breast cancer. GWAS with approximately 6.6 million SNPs in over 3,000 patients and 3,500 controls identified CBLB as associated with MS. CBLB involvement in MS was technically easier to find in Sardinia, but has now been widely replicated in other patient cohorts. Our analyses extend associations of variants with a disease to specify the cell types in which the alleles have their effects. This provides a further step in supplying markers and potential molecular and cellular targets for possible eventual intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000675-07
Application #
8736589
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$550,832
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Sutin, Angelina R; Cutler, Roy G; Camandola, Simonetta et al. (2014) Impulsivity is associated with uric acid: evidence from humans and mice. Biol Psychiatry 75:31-7
Graff, Mariaelisa; Ngwa, Julius S; Workalemahu, Tsegaselassie et al. (2013) Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course. Hum Mol Genet 22:3597-607
Sutin, Angelina R; Zonderman, Alan B; Uda, Manuela et al. (2013) Personality traits and leptin. Psychosom Med 75:505-9
Terracciano, A; Sanna, S; Uda, M et al. (2010) Genome-wide association scan for five major dimensions of personality. Mol Psychiatry 15:647-56
Terracciano, Antonio; Sutin, Angelina R; McCrae, Robert R et al. (2009) Facets of personality linked to underweight and overweight. Psychosom Med 71:682-9
Terracciano, Antonio; Balaci, Lenuta; Thayer, Jason et al. (2009) Variants of the serotonin transporter gene and NEO-PI-R Neuroticism: No association in the BLSA and SardiNIA samples. Am J Med Genet B Neuropsychiatr Genet 150B:1070-7
Ferrucci, Luigi; Giallauria, Francesco; Schlessinger, David (2008) Mapping the road to resilience: novel math for the study of frailty. Mech Ageing Dev 129:677-9
Lettre, Guillaume; Sankaran, Vijay G; Bezerra, Marcos Andre C et al. (2008) DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci U S A 105:11869-74
Lettre, Guillaume; Jackson, Anne U; Gieger, Christian et al. (2008) Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 40:584-91