The genetic architecture of human reproductive behavior – age at first birth (AFB) and number of children ever born (NEB) – has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified and the underlying mechanisms of AFB and NEB are poorly understood. We report the largest genome-wide association study to date of both sexes including 251,151 individuals for AFB and 343,072 for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study, and four additional loci in a gene-based effort. These loci harbor genes that are likely to play a role – either directly or by affecting non-local gene expression – in human reproduction and infertility, thereby increasing our understanding of these complex traits.

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3–6 months; non-cases were included as comparisons (“controls”). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10−8. Suggestive (p<5×10−7) and genome-wide significant (p<5×10−8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10−10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10−11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10−19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10−13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10−10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

Age at first sexual intercourse (AFS) and age at first birth (AFB) have implications for health and evolutionary fitness. In this genome-wide association study (AFS, N=387,338; AFB, N=542,901), we identify 371 SNPs, 11 sex-specific, with a 5-6% polygenic score (PGS) prediction. Heritability of AFB shifted from 9% [CI=4-14] for women born in 1940 to 22% [CI=19-25] in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility, and spermatid differentiation. Our findings suggest that Polycystic Ovarian Syndrome may lead to later AFB, linking with infertility. Late AFB is associated with parental longevity, and reduced incidence of Type 2 Diabetes (T2D) and Cardiovascular disease (CAD). Higher childhood socioeconomic circumstances and those in the highest PGS decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, for understanding longevity, and guiding experimentation into mechanisms of infertility.

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and also identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identify 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology across the life course, including puberty timing, age at first birth, sex hormone regulation and age at menopause. Missense alleles in ARHGAP27 were associated with increased NEB but reduced reproductive lifespan, suggesting a trade-off between reproductive ageing and intensity. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Accordingly, we find that NEB-increasing alleles have increased in frequency over the past two generations. Furthermore, integration with data from ancient selection scans identifies a unique example of an allele-FADS1/2 gene locus-that has been under selection for thousands of years and remains under selection today. Collectively, our findings demonstrate that diverse biological mechanisms contribute to reproductive success, implicating both neuro-endocrine and behavioural influences.

Although kidney transplantation significantly improves the quality of life of patients with end-stage renal disease (ESRD), the prevalence of cardiovascular disease (CVD) in kidney transplant recipients (KTRs) remains high. Atherosclerosis, post-transplantation metabolic changes, immunosuppressive therapy, and periodontitis contribute to elevated cardiovascular risk in this population. The aim of the study was to evaluate carotid intima-media thickness (IMT) as a surrogate marker of atherosclerosis and to analyze the possible risk factors for IMT in Dalmatian KTRs. Ninety-three KTRs were included in this study. Data on clinical and laboratory parameters, body composition, anthropometry, advanced glycation end-product (AGE) measurements, blood pressure, and arterial stiffness were collected. All participants underwent ultrasound examination of IMT and evaluation of periodontal status. KTRs with carotid IMT ≥ 0.9 were significantly older, had a lower level of total cholesterol, fat mass, end-diastolic velocity (EDV), and had fewer teeth. They also had significantly higher values of pulse wave velocity (PWV) and resistive index (RI). We found positive correlations between carotid IMT and duration of dialysis, age, PWV, AGE, RI, and average total clinical attachment level (CAL). The regression model showed that IMT in KTRs is associated with higher PWV, lower fat mass, and fewer teeth. The results of our study suggest that nutritional and periodontal status are associated with carotid IMT in KTRs.

The aim of this cross-sectional study was to determine the body fluid volume in patients diagnosed with both chronic kidney disease (CKD) and arterial hypertension (AH), and to investigate the relationship between fluid overload (FO), nutritional status and arterial stiffness in this specific patient population. A total of 169 participants with CKD and AH were enrolled in the study, and data on general parameters, comorbidities, medication use, and laboratory parameters were collected. Body composition was assessed with a Tanita MC 780 device, and data on the central and peripheral systolic and diastolic blood pressure, as well as pulse wave velocity (PWV) and the augmentation index (AIx) were collected with an IEM Mobil-O-Graph 24 h ambulatory blood pressure monitor, which was based on oscillometry. The Mediterranean Diet Serving Score (MDSS) questionnaire was used to determine the adherence to the Mediterranean diet (MeDi). Our results showed that the significant positive predictors of hydration status were the use of diuretics and oral hypoglycemic agents, whereas the negative predictors were female sex, higher body mass index level and use of two or more antihypertensives in the form of a single-pill combination. We also found differences in blood pressure and arterial stiffness parameters in relation to volume status, along with differences based on the presence of diabetes mellitus (DM). In conclusion, these results call for a higher awareness of volume status in the care of CKD patients with AH, especially in those with diabetes mellitus.

Background and Aims Pulse wave velocity (PWV) is a significant predictor of chronic kidney disease (CKD) progression and death in people with impaired kidney function. It is known that patients with type 2 diabetes mellitus have higher values of PWV. Our study assessed the difference in arterial stiffness parameters (value of peripheral and central blood pressure parameters and PWV) according diabetic status and to evaluate predictors of PWV in hypertensive CKD patients. Method This case control, cross-sectional study included 252 hypertensive CKD patients 143 (56.7%) men and 109 (43.3%) women, aged 67 years (IQR = 15). For each participant data about sex, age, height, presence of CKD, AH and other comorbidities were collected. Laboratory parameters (urea, creatinine, estimated glomerular filtration rate (eGFR), glycated hemoglobin (HbA1c)) were obtained from peripheral blood and 24-hour urine samples were collected to analyze albuminuria. Each participant underwent 24-hour ambulatory blood pressure measurement using the IEM Mobil-O-Graph based on the oscillometry. Tanita MC780 Multi Frequency segmental body composition analyzer was used to measure body weight and level of visceral fat. Body mass index (BMI) was calculated. Results Out of 252 participants with AH and CKD, 107 (42.5%) also had DM. Participants with DM were older (p&lt;0001), had higher pulse pressure (p&lt;0.001) and PWV (p&lt;0.001) while the levels of peripheral and central diastolic pressure (p&lt;0.001) were lower. Regarding body composition parameters, DM participants had higher BMI (p = 0.001) and visceral fat level (p&lt;0.001). Positive predictors of PWV adjusted for age, sex, presence of DM and eGFR were HbA1c (β = 0.216, p = 0.007), albuminuria (β = 0.000, p = 0.002), central and peripheral systolic and diastolic blood pressure (β = 0.035, p&lt;0.001; β = 0.035, p&lt;0.001; β = 0.033, p&lt;0.001; β = 0.035, p&lt;0.001), pulse pressure (β = 0.047, p&lt;0.001) and mean arterial pressure (β = 0.042, p&lt;0.001). Body composition parameters were not found to be significant predictors of PWV. Conclusion We found significant differences in 24-hour blood pressure parameters and body composition in relation to the presence of DM. One possible explanation for the lower peripheral and central diastolic blood pressure in diabetic participants is the older age of these participants. Accordingly, PWV as a parameter of arterial stiffness, which is higher in DM participants, could also be due to the age difference. As for the predictors of PWV, the expected predictors were parameters of blood pressure. HbA1c and albuminuria were also associated with PWV as parameter of arterial stiffness in CKD participants with AH.

There is limited evidence on the associations between dietary patterns, body composition, and nonclassical predictors of worse outcomes such as advanced glycation end products (AGE) in kidney transplant recipients (KTRs). The aim of this cross-sectional study was to determine the level of AGE-determined cardiovascular (CV) risk in Dalmatian KTRs and possible associations between AGE, adherence to the Mediterranean diet (MeDi), and nutritional status. Eighty-five (85) KTRs were enrolled in this study. For each study participant, data were collected on the level of AGE, as measured by skin autofluorescence (SAF), Mediterranean Diet Serving Score (MDSS), body mass composition, anthropometric parameters, and clinical and laboratory parameters. Only 11.76% of the participants were adherent to the MeDi. Sixty-nine percent (69%) of KTRs had severe CV risk based on AGE, while 31% of KTRs had mild to moderate CV risk. The results of the LASSO regression analysis showed that age, dialysis type, dialysis vintage, presence of CV and chronic kidney disease, C- reactive protein level, urate level, percentage of muscle mass, and adherence to recommendations for nuts, meat, and sweets were identified as positive predictors of AGE. The negative predictors for AGE were calcium, phosphate, cereal adherence according to the MeDi, and trunk fat mass. These results demonstrate extremely low adherence to the MeDi and high AGE levels related CV risk in Dalmatian KTRs. Lifestyle interventions in terms of CV risk management and adherence to the MeDi of KTRs should be taken into consideration when taking care of this patient population.