1) Pulse wave velocity, a noninvasive index of central arterial stiffness, is a potent predictor of cardiovascular mortality and morbidity. We conducted a genome-wide association study to identify common genetic variation associated with pulse wave velocity. Analyses were performed in 4221 participants in the SardiNIA study, a founder population. We found that the nonsynonymous single-nucleotide polymorphisms rs3742207 in the COL4A1 gene was significantly associated with pulse wave velocity. This locus was successfully replicated both in an independent sample within the SardiNIA cohort and in the Old-Order Amish population, an external genetically distant founder population of European ancestry, with an overall P=5.16E-8. Collagen type 4 is the major structural component of basement membranes, suggesting that previously unrecognized cell-matrix interactions may exert an important role in regulating arterial stiffness, which is an established independent predictor of adverse cardiovascular outcomes. Further work is needed to elucidate these mechanisms, but this could potentially lead to the development of novel interventions aimed at delaying or preventing the risks associated with accelerated arterial stiffening. 2) We investigated the gender-specific control of cardiovascular (CV) risk factors and subclinical vascular lesions in a founder population in Italy. Prevalence was: hypertension (HT) 29.2%, diabetes mellitus (DM) 4.8%, dyslipidemia (LIP) 44.1% and was higher in men than in women. Disease prevalence increased with age for every CV risk factor. Men were less likely than women to take anti-HT drugs and to reach blood pressure (BP) control (9.9%vs.16%). Only 17.6% of HT >65years had a BP 65years, those with the highest treatment rate). The ratio of control-to-treated HT was lower in subjects with, than in those without, thicker carotid arteries (31.5% vs. 38.8%, p<0.05) or stiffer aortas (26.0% vs. 40.0%, p<0.05) or carotid plaques (26.3% vs. 41.1%, p<0.05). We found, that a large number of subjects at high CV risk are not treated and the management of subclinical vascular lesions is far from optimal. 3) The electrocardiographic PR interval reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation (AF). To identify underlying common genetic variation, we meta-analyzed genome-wide association results for PR interval from seven community-based studies of European-ancestry individuals: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study and SardiNIA (N=28,517). Associated loci were tested for association with AF (N=5,741 AF cases). Significant association with PR interval was identified at nine loci (P<5E-8). At chromosome 3p22.2, we identified two independent signals in SCN10A and SCN5A. Six loci were near cardiac developmental genes CAV1/CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5/TBX3. Another signal was at ARHGAP24, a locus without known relevance to the heart. Five of the nine loci, SCN5A, SCN10A, NKX2-5, CAV1/CAV2, and SOX5, were also associated with AF (P<0.0056). Common genetic variation, particularly in voltage gated sodium channels and in developmental genes, contributes significantly to atrial and atrioventricular conduction and to AF risk. 4) The QT interval, a measure of cardiac repolarization, predisposes to ventricular tachycardia and sudden cardiac death (SCD) when physiologically prolonged or shortened . Previously, we identified a common genetic variant in NOS1AP (CAPON) explaining 1% of the QT interval variance in an European population. To identify additional loci, we analyzed genome-wide association data from five studies, ARIC, KORA, SardiNIA, GenNova and HNR (total n = 15,842). Our results confirm the NOS1AP association and identify evidence for association (P<5.0E-8) with variants at nine additional loci. Four loci map at or near the monogenic long QT syndrome genes KCNQ1 (LQT1, SQT2), KCNH2 (LQT2, SQT1), SCN5A (LQT3) and KCNJ2 (LQT7, SQT3). Two other loci include genes with well established myocardial electrophysiological functions: the Na+/K+ ATPase beta subunit 1 (ATP1B1) and the sarcoplasmatic reticulum Ca2+ ATPase regulator phospholamban (PLN). The remaining three loci, LITAF, NDRG4/GINS3 and RNF207, have not been previously implicated in human myocardial electrophysiology. Three of the ten loci carried independent second effects raising the number of identified QT associated variants to 13. These results provide new insights into myocardial electrophysiology and provide novel candidate genes for SCD. 5) Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N
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