Genetically instrumented LDL-cholesterol lowering and multiple disease outcomes: A Mendelian randomization phenome-wide association study in the UK Biobank.

AIMS: Lipid-lowering medications are widely used to control blood cholesterol levels and manage a range of cardiovascular and lipid disorders. We aimed to explore the possible associations between LDL lowering and multiple disease outcomes or biomarkers. METHODS: We performed a Mendelian randomization phenome-wide association study (MR-PheWAS) in 337 475 UK Biobank participants to test for associations between four proposed LDL-C-lowering genetic risk scores (PCSK9, HMGCR, NPC1L1 and LDLR) and 1135 disease outcomes, with follow-up MR analyses in 52 serum, urine, imaging and clinical biomarkers. We used inverse-variance weighted MR in the main analyses and complementary MR methods (weighted median, weighted mode, MR-Egger and MR-PRESSO) as sensitivity analyses. We accounted for multiple testing with false discovery rate correction (P < 2.0 × 10-4 for phecodes, P < 1.3 × 10-2 for biomarkers). RESULTS: We found evidence for an association between genetically instrumented LDL lowering and 10 distinct disease outcomes, suggesting potential causality. All genetic instruments were associated with hyperlipidaemias and cardiovascular diseases in the expected directions. Biomarker analyses supported an effect of LDL-C lowering through PCSK9 on lung function (FEV [beta per 1 mg/dL lower LDL-C -1.49, 95% CI -2.21, -0.78]; FVC [-1.42, 95% CI -2.29, -0.54]) and through HMGCR on hippocampal volume (beta per 1 mg/dL lower LDL-C 6.09, 95% CI 1.74, 10.44). CONCLUSIONS: We found genetic evidence to support both positive and negative effects of LDL-C lowering through all four LDL-C-lowering pathways. Future studies should further explore the effects of LDL-C lowering on lung function and changes in brain volume.

Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus.

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

Burden and trend of diet-related non-communicable diseases in Australia and comparison with 34 OECD countries, 1990-2015: findings from the Global Burden of Disease Study 2015.

BACKGROUND: Diet is a major determining factor for many non-communicable chronic diseases (NCDs). However, evidence on diet-related NCD burden remains limited. We assessed the trends in diet-related NCDs in Australia from 1990 to 2015 and compared the results with other countries of the Organization for Economic Co-operation and Development (OECD). METHODS: We used data and methods from the Global Burden of Disease (GBD) 2015 study to estimate the NCD mortality and disability-adjusted life years (DALYs) attributable to 14 dietary risk factors in Australia and 34 OECD nations. Countries were further ranked from the lowest (first) to highest (35th) burden using an age-standardized population attributable fraction (PAF). RESULTS: In 2015, the estimated number of deaths attributable to dietary risks was 29,414 deaths [95% uncertainty interval (UI) 24,697 - 34,058 or 19.7% of NCD deaths] and 443,385 DALYs (95% UI 377,680-511,388 or 9.5% of NCD DALYs) in Australia. Young (25-49 years) and middle-age (50-69 years) male adults had a higher PAF of diet-related NCD deaths and DALYs than their female counterparts. Diets low in fruits, vegetables, nuts and seeds and whole grains, but high in sodium, were the major contributors to both NCD deaths and DALYs. Overall, 42.3% of cardiovascular deaths were attributable to dietary risk factors. The age-standardized PAF of diet-related NCD mortality and DALYs decreased over the study period by 28.2% (from 27.0% in 1990 to 19.4% in 2015) and 41.0% (from 14.3% in 1990 to 8.4% in 2015), respectively. In 2015, Australia ranked 12th of 35 examined countries in diet-related mortality. A small improvement of rank was recorded compared to the previous 25 years. CONCLUSIONS: Despite a reduction in diet-related NCD burden over 25 years, dietary risks are still the major contributors to a high burden of NCDs in Australia. Interventions targeting NCDs should focus on dietary behaviours of individuals and population groups.