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Background There is conflicting evidence regarding the association between vitamin D status and cognitive function in population studies. The use of one-time vitamin D measurement in cognitive health studies may not reflect long-term vitamin D status in the body. Objective We aimed to examine the relationship of vitamin D status measured over time with the risk of neurocognitive disorders (NCDs) in Norwegian older adults. Design Prospective cohort study. Setting Regional, Trøndelag Health Study. Participants This study followed a random cohort of 717 participants from HUNT2 (1995–97) and HUNT3 (2006–08) to HUNT4 70+ (2017–19). The mean age at HUNT4 70+ was 77.7 years. Methods Seasonal-standardized serum 25-hydroxyvitamin D [25(OH)D] levels in HUNT2 and HUNT3 were averaged and used as either a categorical variable ( Results In total, 347 (48.4%) had NCDs in HUNT4, with 33.3% having MCI and 15.1% having dementia. Compared with participants with serum 25(OH)D ≥50 nmol/L, those with 25(OH)D Conclusion Vitamin D insufficiency defined by two times measurements of serum 25(OH)D with a 10-year interval was not associated with the risk of NCDs in a cohort of older Norwegian adults. Future studies utilizing multiple vitamin D measurements with a longer follow-up duration and larger sample size are warranted.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Central Norway Regional Health Authority Norwegian Health Association Introduction Cardiovascular disease (CVD) is the leading cause of death worldwide. Several studies have shown that low cardiorespiratory fitness (CRF) is a major risk factor for CVD and is suggested to be a stronger predictor of CVD morbidity and mortality than established cardiovascular risk factors. CRF quantified as maximal oxygen uptake (VO2max) has a strong genetic component, estimated to be ~50%. Unfortunately, current studies on genetic markers for CRF are limited by small sample sizes. In addition, there are few studies on directly measured VO2max, as most of the previous studies are based on estimated CRF. To overcome these limitations, we performed a large-scale systematic screening for genetic variants associated with VO2max aiming to provide awaited insight to this complex trait and discover possible links between VO2max and CVD. Purpose To identify and validate genetic factors associated with VO2max. Methods The genotypes of 70,000 participants from the Trøndelag Health study (HUNT) were imputed providing information on 25 million single-nucleotide polymorphisms (SNPs). We conducted a genome-wide association study (GWAS) including 4,525 participants with directly measured VO2max from the HUNT3 Fitness study. The GWAS was performed using BOLT-LMM, adjusted for age, gender, physical activity, principal components, and genotyping batch. In addition, we ran a GWAS with the same covariates except physical activity. Further, gender specific analyses were conducted. For validation, similar analyses were performed in the United Kingdom Biobank (UKBB). In the UKBB, CRF was assessed through a submaximal bicycle test. The analyses of UKBB included ~60,000 participants and over 90 million SNPs. Functional analyses of the GWAS results were examined by functional mapping and annotation (FUMA). Results Two GWAS-significant (p < 5×10-8) SNPs associated with VO2max were identified in the total population, two in the male population, and 24 in the female population in HUNT. Two of the 24 SNPs found in the female population were nominally significant in the UKBB. One of the validated SNPs in the female population is located inside PIK3R5, that is shown to be of importance in cardiac function and CVD. In addition, the functional analyses in the total- and male population revealed candidate SNPs in a gene previously found to be associated with endurance, PPP3CA. Conclusions We have identified 28 novel SNPs associated with VO2max in the HUNT cohort. Two of these SNPs were nominally validated in females in UKBB. One of the validated SNPs resides within a gene previously reported to be related to heart function and CVD. In addition, the functional analyses in the total- and male population revealed candidate SNPs in a gene previously found to be associated with endurance. Further functional analyses using bioinformatic approaches may provide more information on the physiological importance of these findings and their relation to CVD.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Central Norway Regional Health AuthorityNorwegian Health Association Introduction Cardiovascular disease (CVD) is the leading cause of death worldwide. Several studies have shown that low cardiorespiratory fitness (CRF) is a major risk factor for CVD. Low CRF is suggested to be a stronger predictor of CVD morbidity and mortality than established cardiovascular risk factors like obesity, diabetes, and cholesterol. Several studies suggest that CRF quantified as maximal oxygen uptake (VO2max) has a strong genetic component, estimated to be ~50%. Unfortunately, current studies on genetic markers for CRF are limited by small sample sizes. In addition, there are few studies on directly measured VO2max, as most of the previous studies are based on estimated CRF. Directly measured VO2max is considered as the gold standard for measuring CRF. Thus, a large-scale systematic screening for genetic variants associated with VO2max may provide awaited insight to this complex trait and discover possible links between VO2max and CVD. Purpose To identify and validate genetic factors associated with VO2max. Methods The genotypes of 70.000 participants from the Trøndelag Health study (HUNT) were imputed providing information on 25 million SNPs. We conducted a genome-wide association study (GWAS) including 4525 participants with directly measured VO2max from the HUNT3 Fitness study. The GWAS was performed using BOLT-LMM, adjusted for age, gender, physical activity, principal components, and genotyping batch. In addition, we ran a GWAS with the same covariates except physical activity. Further, gender specific analyses were conducted. For validation, similar analyses were performed in the United Kingdom Biobank (UKBB). In the UKBB, CRF was assessed through a submaximal bicycle test. The analyses of UKBB included ~60.000 participants and over 90 million SNPs. Results Two GWAS-significant (p < 5x10-8) SNPs associated with VO2max were identified in the total population in HUNT. Further, 24 GWAS-significant SNPs associated with VO2max in females, and two GWAS-significant SNPs associated with VO2max in males were discovered. Two of the 24 SNPs found in the female population were nominally significant in the UKBB. The validated SNPs are rs376927175, an intergenic SNP downstream of APBA1, and rs551942830 (proxy for rs190675254 with LD = 1.0), a 3 Prime UTR variant inside PIK3R5. PIK3R5 encodes the regulatory subunit of one class of PI3Ks, that is shown to be of importance in cardiac function and CVD. None of the SNPs found in the total population nor the male population were validated in UKBB. Conclusions We have identified 28 novel SNPs associated with VO2max in the HUNT cohort. Two of these SNPs were nominally validated in females in UKBB. One of the validated SNPs resides within a gene previously reported to be related to heart function and CVD. Further functional analyses using bioinformatic approaches may provide more information on the physiological importance of these findings and their relation to CVD.