In a first survey, the project team recruited over 6,100 subjects from a catchment area including four towns in east-central Sardinia and assessed a first list of >200 traits. The baseline survey has been followed by follow-up visits that collected longitudinal data on the same traits collected at baseline but added assessment of frailty-related traits, namely measures of bone density and geometry, muscle strength, and gait speed, and additional cardiovascular measures (see below). In the course of SardiNIA3, along with the expansion of the cohort and the addition of more traits (see below), increases in testing efficiency and additional cost-sharing funds from Sardinian sources permit the completion of Fourth Visits for the entire cohort. Also in current actions, DNA sequencing has recovered essentially all of the genetic variation in the cohort, and further arrangements for an Outcome Study have also been made to be implemented in SardiNIA4, a further 5-year continuation of the Project that also projects Fifth Visits for the cohort.
The infrastructure for the clinic and phenotypic testing has been stable, with stringent quality control, which is reflected in the high quality of the database. The initial sample cohort included over 62% of the eligible population living in the region (age 14-102 years), and at least 96% of the initial cohort have all grandparents born in the same province. The initial group included 4,933 phenotyped sib pairs, 4,266 phenotyped parent-child pairs, >4,069 phenotyped cousin pairs, and >6,459 phenotyped avuncular pairs. Additional recruitment has increased the cohort substantially, and results have consistently shown that for essentially every trait, most of the associated genes and variants would be involved in determining variance in both young and old and in men and women. Thus, genetic analyses can draw on data from all ages and both genders.
The added value of studying a founder population has also been demonstrated by the extension of DNA analysis to the full range of variation by sequencing. The population has proven to contain the great bulk of variation found in other populations, but during its isolation over many thousands of years, many variants rare elsewhere have risen to relatively high levels on the island by drift or selection and others have newly arisen as Sardinian-specific. These have provided extensive new information about a whole range of traits and pathways (e.g., Nature Genetics November, 2015 articles and Editorial).
Sardinia also offers a special entre to the genetics of specific diseases that are especially prevalent in the founder population. This includes the anomalously high incidence of autoimmune diseases including Multiple Sclerosis and Type 1 diabetes, which interrupt the high to low gradient of incidence from Northern to Southern Europe. Again, this has fostered novel findings in causation and pathophysiology.
The founder population itself also contains within its DNA a record of human demography through history, which has permitted the inference of the timing of human population movements based on mitochondrial and Y chromosome analyses.
Regarding the course and mechanism of aging, the longitudinal study, now in its 15th year, focuses on residents of the cluster of towns to collect longitudinal information on more than 400 age-related quantitative traits ("endophenotypes" or "quantitative risk-related genetic or environmental factors") that can be scored on a continuous scale, as well as >200 dichotomous traits (including major diseases and risk factors such as smoking). The use of quantitative traits permits the study of the entire range of allelic variation in a population, with particular interest in a range of cardiovascular risk factors, anthropometric measurements, blood test values, facets of personality, and bone-density and frailty-related variables.
The longitudinal study of a broad range of phenotypes in a founder population is distinctive in this study, and stable environmental/epidemiological factors combined with the simplification of genetic analyses also aid in proposed joint investigations of relative risk. Furthermore, because we are collecting risk factor data, we can also analyze, in an Outcome Study, the prognostic power and/or pathophysiological relevance of earlier predictors for the onset of serious risk factors [e.g., increases in pulse wave velocity as a function of earlier (predictor) lipid and inflammatory markers].
See the rest here:
National Institutes of Health - SardiNIA
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