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, a variety of epidemiological and genetic factors have been identified. In the last year, epidemiological studies have been done of personality traits associated with white coat or masked hypertension, with circadian blood pressure patterns, or with uric acid levels;of the prevalence of chronic kidney disease and unknown thyroid disorders;and of arterial stiffness and influences of the metabolic syndrome. As for genetic studies, 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, 3,500 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. In the past year, some GWAS consortium studies have advanced technical approaches, including the usefulness of averaging of quantitative blood pressure traits;quality control;integrative annotation of variants;and mining the human phenome using allelic scores. As for GWAS of genetic factors involved in traits and diseases, Consortium efforst in the last year has discovered variants associated with the QT interval;thyroid peroxidase antibodies and clinical thyroid disease;fibrinogen levels;and BMI in adolescents and young adults. 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 detail, in a 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.

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National Institute on Aging (NIA)
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van den Berg, Stéphanie 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
(2016) Genome-wide association study identifies 74 loci associated with educational attainment. Nature 533:539-42
Delitala, Alessandro P; Terracciano, Antonio; Fiorillo, Edoardo et al. (2016) Depressive symptoms, thyroid hormone and autoimmunity in a population-based cohort from Sardinia. J Affect Disord 191:82-7
McCarthy, Shane; Das, Sayantan; Kretzschmar, Warren et al. (2016) A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet 48:1279-83
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
Scuteri, Angelo; Morrell, Christopher H; Orru', Marco et al. (2016) Gender specific profiles of white coat and masked hypertension impacts on arterial structure and function in the SardiNIA study. Int J Cardiol 217:92-8
Hinney, A; Kesselmeier, M; Jall, S et al. (2016) Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index. Mol Psychiatry :
Genetics of Personality Consortium; de Moor, Marleen H M; van den Berg, Stéphanie M et al. (2015) Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder. JAMA Psychiatry 72:642-50
(2015) The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study. PLoS Genet 11:e1005378
Danjou, Fabrice; Zoledziewska, Magdalena; Sidore, Carlo et al. (2015) Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels. Nat Genet 47:1264-71

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