Governance and current state of the Project
The governance of the Project began with its implementation under the auspices of the National Institute on Aging (NIA), leading to the name SardiNIA (i.e., Sardi + NIA). A contract to Giuseppe Pilia, M.D., Principal Investigator for the Italian National Research Council (CNR) Institute in Cagliari (now the Institute of Genetic and Biomedical Research (IRGB), with David Schlessinger, Ph.D., Chief of the Laboratory of Genetics at NIA, as Principal Investigator for NIA and along with the indispensable support of Antonio Cao, M.D., the Dean of human genetics studies in Italy. [Single-handed, he organized the analysis of “Sardinian diseases”, Mendelian maladies enriched in the founder population, and drove the campaign that reduced beta-thalassemia on the island by 95%, an achievement recognized by the American Society for Human Genetics in 1993 with its prestigious William Allan Award.]

During the initial 5 years of the study (mid-2001 to mid-2006), a clinic was set up in the town of Lanusei and a team of Investigators ("Progenia") assembled there to recruit participants and collect data from it and 3 other clustered villages in eastern Sardinia. After the untimely early death of Dr. Pilia, Dr. Manuela Uda took over for the next years, and was succeeded in 2010 by Francesco Cucca, M.D., Professor of Medical Genetics at the University of Sassari and then Director of IRGB-CNR. Dr. Cucca has continued as the P.I. of the study after the Directorship of IRGB shifted in 2021 to Dr. Marcella Devoto, a human geneticist who has maintained the linkage to the CNR in the governance of the Project. The Core Clinic in Lanusei is managed by Edoardo Fiorillo, Ph.D., with a staff of physicians, nurses, biologists, and informatics specialists. 

Meanwhile, at the NIA, since Dr. Schlessinger’s retirement in 2018, Drs. Myriam Gorospe, Chief of the Laboratory of Genetics and Genomics, and Lenore Launer, Chief of the Laboratory of Epidemiology and Population Science, have become Co-P.I.’s for the study at NIA.  

The Project has been fortified by collaborators at NIA and elsewhere who are expert in statistical genetics, genomics, and aging research. Soon after the project commenced, Drs. Pilia and Schlessinger were joined by a senior statistical geneticist, Goncalo Abecasis, Ph.D., at the University of Michigan, to head up data analysis efforts and train several Sardinian geneticists, while other Sardinians grew to capable members of the team of Ph.D. analysts in Cagliari, Sardinia. They include Serena Sanna, Carlo Sidore, Mauro Pala, Matteo Floris, and Maristella Steri. Meanwhile, another Statistical Genetics unit, headed by Jun Ding, Ph.D., was added at the Laboratory of Genetics of the NIA in Baltimore. Currently, the collaborative group comprising the leadership of the Project includes individuals working with investigators at several U.S. Universities (especially, Stephen Montgomery, Ph.D., at Stanford University, and John Novembre, Ph.D., at the University of Chicago), as well as several graduates of Dr. Abecasis’ group, including Sarah Gagliano Taliun at the University of Montreal, along with heads of Intramural Program Laboratories at the NIA, especially Edward Lakatta, M.D. (Cardiovascular Science), as well as Drs. Gorospe and Launer and members of the Translational Gerontology Branch (headed by Luigi Ferrucci, M.D., the Scientific Director of NIA). 

Concerning distribution of effort in ongoing and planned work, data collection continues at the SardiNIA/ProgeNIA clinic in Lanusei, where the genotyping work is also performed, and at island-wide sites for the collection of disease-specific and blood bank control samples. In a critical joint effort of the Sardinian and U. Michigan sites, DNA sequencing recovered the full set of genetic variants (about 12,500,000) in the population at levels greater than MAF 0.4% - the level required to do genetic association analyses.  

NIA investigators, led by Drs. Gorospe and Launer, continue to be involved in choosing and analyzing traits and test protocols for frailty, cardiovascular, and psychological traits, and in the maintenance of the master database and preparation of summaries of heritability and age- and gender-specific distributions for all traits. They also collaborate on immunosenescence studies performed in Sardinia; in the development of algorithms for targeted types of analyses; and in the preparation of all manuscripts. The SardiNIA investigators operating in Sardinia, led by Dr. Cucca, are the primary producers and analysts of all genetic and phenotypic data, with the supervision of all clinical activities performed in the Center in Lanusei. They are also the primary investigators in traits and test protocols for hematological, inflammatory, immunological (both cellular and humoral), and anthropometric (including those related to internal organs) phenotypes, as well as those related to kidney function. They also participate actively in the design and analysis of cardiovascular traits, with special emphasis in echocardiographic cardiovascular measures. They also take the lead in writing papers and obtaining additional funding to study traits of paramount relevance for this component of the project. 

The Core Project is supported by the ongoing contract from the National Institute on Aging with cost-sharing by the IRGB, aided by cost-sharing from the Italian National Research Council and awards and collaborative grants from other funding sources for specific topics. They include support for extensive study of immune cells and molecules and refined study of immune system cell types in cohort members.  

Auxiliary studies that have continued to benefit from the cohort and population structure and repeated visits include analyses of human demographic history, involving the group of Dr. John Novembre at the University of Chicago, and analyses of genetic and environmental effects on RNA levels with the team of Dr. Stephen Montgomery at Stanford. 

The two primary goals remain:

1. Measures of genetic variation, quantitative traits, and trends for traits and outcomes,focusing on the longitudinal dimension of the study, aiming at determining individual trajectories and features of the aging process, as well as the identification of longer-term health-related outcome.

The number of individuals in the overall datasets (combining the SardiNIA cohort and the various case-control studies) has increased to ~17,000, before the new initiative to extend recruitment to over 100,000. The core group of ~6,000 individuals of the SardiNIA cohort has been supplemented with an additional ~700 volunteers from the same area to integrate those who could not participate in the various stages of the follow-up with a targeted emphasis on individuals older than 90. Overall, these individuals have had full-genome scans with a chip accessing the full set of variants determined for the population, and the same chip is being used to recover the genetic endowment of new cases and controls across the island.

 We have maintained a concentration on risk factors for age-related diseases and traits/risk factors. For traits, we have specifically profited from the experience in long-standing epidemiological studies at the NIA (for example, incorporating frailty-related tests), and have made trait lists concordant with the lists of traits studied in the Baltimore Longitudinal Study of Aging and the AGES and InCHIANTI studies to facilitate cross-replication and meta-analyses among the studies sponsored by the NIA.

 The focus remains on cardiovascular traits, personality traits, sensory capacity (retinal scans and hearing tests), levels of immune system cells, frailty-related traits (walking speed, grip strength, and bone density), and kidney ultrasound features. For all of the standard traits, including cardiovascular, personality, sensory capacity, frailty-related, and kidney ultrasound measures, full GWAS of all traits have been completed.

 As an example, the sample traits of levels of immune system cells has been extensively studied. GWAS analysis on 1,200 individuals with the 12,500,000 SNP set revealed 23 loci with a large effect on at least one cell type. In addition, the SH2B3 variant R262W, already found 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. Extensions of this approach have now extended analyses to a much larger cohort, with up to 100 significant loci identified, and to additional types of cells, including B cell subtypes, and cytokines.

2. Gene variation associated with phenotypic traits, prevalent diseases, and age-related trends, Case-control studies have concentrated on diseases strikingly common in Sardinia such as autoimmune multiple sclerosis and type 1 diabetes as well as thalassemia. They also include diseases of more global high prevalence such as common hypertension, chronic kidney disease and breast cancer; and in the latest 5-year tenure of the study, cases and controls are being collected for a study of Alzheimer/dementia (described further in the “Introduction” section at this web site).

 For case-control studies, the entire island remains the catchment to recruit enough cases from among well-characterized clinical series collected by Sardinian physicians, compared with unaffected Sardinians represented by healthy blood donors collected either in the main Transfusion Centers on the island or as controls collected specifically for specific disease studies.

 The results of the case-control studies and those of related quantitative traits generated in the SardiNIA project are analyzed jointly with other GWAS efforts to reveal coincident associations, indicative of molecules, cells and pathways primarily involved in a disease process. The results of these studies as well as those focusing on aging have the potential to translate into substantial clinical uses. Especially notable, for example, several SNPs that affect the levels of particular immune cell types have also been associated with autoimmune diseases in Consortium studies; the analyses extend associations of variants with a disease to specify the cell types in which the alleles have their effects. This provides markers and potential cellular and molecular targets for further analyses and possible intervention.

 Additional major initiatives, including an island-wide study of Alzheimer/dementia cases and controls, are described in the Home page introductory section.

A complete list of the publications in whole or in part from the Project (as of May 10, 2023) is given under the PUBLICATIONS rubric at this web site.