Polygenic and socioeconomic risk for high body mass index:69 years of follow-up across life

Genetic influences on body mass index (BMI) appear to markedly differ across life, yet existing research is equivocal and limited by a paucity of life course data. We thus used a birth cohort study to investigate differences in association and explained variance in polygenic risk for high BMI across infancy to old age (2-69 years). A secondary aim was to investigate how the association between BMI and a key purported environmental determinant (childhood socioeconomic position) differed across life, and whether this operated independently and/or multiplicatively of genetic influences. Data were from up to 2677 participants in the MRC National Survey of Health and Development, with measured BMI at 12 timepoints from 2-69 years. We used multiple polygenic indices from GWAS of adult and childhood BMI, and investigated their associations with BMI at each age. For polygenic liability to higher adult BMI, the trajectories of effect size (β) and explained variance (R2) diverged: explained variance peaked in early adulthood and plateaued thereafter, while absolute effect sizes increased throughout adulthood. For polygenic liability to higher childhood BMI, explained variance was largest in adolescence and early adulthood; effect sizes were marginally smaller in absolute terms from adolescence to adulthood. All polygenic indices were related to higher variation in BMI; quantile regression analyses showed that effect sizes were sizably larger at the upper end of the BMI distribution. Socioeconomic and polygenic risk for higher BMI across life appear to operate additively; we found little evidence of interaction. Our findings highlight the likely independent influences of polygenic and socioeconomic factors on BMI across life. Despite sizable associations, the BMI variance explained by each plateaued or declined across adulthood while BMI variance itself increased. This is suggestive of the increasing importance of chance ('non-shared') environmental influences on BMI across life

Relations and Equivalences Between Circuit Lower Bounds and Karp-Lipton Theorems

A frontier open problem in circuit complexity is to prove P^{NP} is not in SIZE[n^k] for all k; this is a necessary intermediate step towards NP is not in P_{/poly}. Previously, for several classes containing P^{NP}, including NP^{NP}, ZPP^{NP}, and S_2 P, such lower bounds have been proved via Karp-Lipton-style Theorems: to prove C is not in SIZE[n^k] for all k, we show that C subset P_{/poly} implies a "collapse" D = C for some larger class D, where we already know D is not in SIZE[n^k] for all k. It seems obvious that one could take a different approach to prove circuit lower bounds for P^{NP} that does not require proving any Karp-Lipton-style theorems along the way. We show this intuition is wrong: (weak) Karp-Lipton-style theorems for P^{NP} are equivalent to fixed-polynomial size circuit lower bounds for P^{NP}. That is, P^{NP} is not in SIZE[n^k] for all k if and only if (NP subset P_{/poly} implies PH subset i.o.- P^{NP}_{/n}). Next, we present new consequences of the assumption NP subset P_{/poly}, towards proving similar results for NP circuit lower bounds. We show that under the assumption, fixed-polynomial circuit lower bounds for NP, nondeterministic polynomial-time derandomizations, and various fixed-polynomial time simulations of NP are all equivalent. Applying this equivalence, we show that circuit lower bounds for NP imply better Karp-Lipton collapses. That is, if NP is not in SIZE[n^k] for all k, then for all C in {Parity-P, PP, PSPACE, EXP}, C subset P_{/poly} implies C subset i.o.-NP_{/n^epsilon} for all epsilon > 0. Note that unconditionally, the collapses are only to MA and not NP. We also explore consequences of circuit lower bounds for a sparse language in NP. Among other results, we show if a polynomially-sparse NP language does not have n^{1+epsilon}-size circuits, then MA subset i.o.-NP_{/O(log n)}, MA subset i.o.-P^{NP[O(log n)]}, and NEXP is not in SIZE[2^{o(m)}]. Finally, we observe connections between these results and the "hardness magnification" phenomena described in recent works

Associations of Infant Nutrition with Insulin Resistance Measures in Early Adulthood: Evidence from the Barry-Caerphilly Growth (BCG) Study

Background: Previous studies suggest that over-nutrition in early infancy may programme long-term susceptibility to insulin resistance. Objective: To assess the association of breast milk and quantity of infant formula and cows ’ milk intake during infancy with insulin resistance measures in early adulthood. Design: Long-term follow-up of the Barry Caerphilly Growth cohort, into which mothers and their offspring had originally been randomly assigned, between 1972–1974, to receive milk supplementation or not. Participants were the offspring, aged 23–27 years at follow-up (n = 679). Breastfeeding and formula/cows ’ milk intake was recorded prospectively by nurses. The main outcomes were insulin sensitivity (ISI0) and insulin secretion (CIR30). Results: 573 (84%) individuals had valid glucose and insulin results and complete covariate information. There was little evidence of associations of breastfeeding versus any formula/cows ’ milk feeding or of increasing quartiles of formula/cows’ milk consumption during infancy (,3 months) with any outcome measure in young adulthood. In fully adjusted models, the differences in outcomes between breastfeeding versus formula/cows ’ milk feeding at 3 months were: fasting glucose (20.07 mmol/l; 95 % CI: 20.19, 0.05); fasting insulin (8.0%; 28.7, 27.6); ISI0 (26.1%; 211.3, 12.1) and CIR30 (3.8%; 219.0, 32.8). There was also little evidence that increasing intakes of formula/cows ’ milk at 3 months were associated with fastin

Linear and Non-linear associations between vitamin D and grip strength: a Mendelian Randomisation study in UK Biobank

BACKGROUND: Low vitamin D status is a widespread phenomenon. Similarly, muscle weakness, often indicated by low grip strength, is another public health concern; however, the vitamin D-grip strength relationship is equivocal. It is important to understand whether variation in vitamin D status causally influences muscle strength to elucidate whether supplementation may help prevent/treat muscle weakness. METHODS: UK Biobank participants, aged 37-73 years, with valid data on Vitamin D status (circulating 25-hydroxyvitamin D (25(OH)D) concentration) and maximum grip strength were included (N=368,890). We examined sex-specific cross-sectional associations between 25(OH)D and grip strength. Using Mendelian randomisation (MR), we estimated the strength of the 25(OH)D-grip strength associations using genetic instruments for 25(OH)D as our exposure. Crucially, because potential effects of vitamin D supplementation on strength could vary by underlying 25(OH)D status, we allowed for non-linear relationships between 25(OH)D and strength in all analyses. RESULTS: Mean(SD) of 25(OH)D was 50(21)nmol/L in males and females. In cross-sectional analyses there was evidence of non-linear associations between 25(OH)D and strength: e.g., compared to males with 50nmol/L circulating 25(OH)D, males with 75nmol/L had 0.36kg (0.31,0.40) stronger grip; males with 25nmol/L had 1.01kg (95% CI: 0.93,1.08) weaker grip. In MR analyses, linear and non-linear models fitted the data similarly well: e.g., 25nmol/L higher circulating 25(OH)D in males was associated with 0.25kg (-0.05,0.55) greater grip (regardless of initial 25(OH)D status). Results were similar, albeit weaker, for females. CONCLUSIONS: Using two different methods to triangulate evidence, our findings suggest moderate to small causal links between circulating 25(OH)D and grip strength

Influence of Fuel Injection System and Engine-Timing Adjustments on Regulated Emissions from Four Biodiesel Fuels

The use of biofuels for transportation has grown substantially in the past decade in response to federal mandates and increased concern about the use of petroleum fuels. As biofuels become more common, it is imperative to assess their influence on mobile source emissions of regulated and hazardous pollutants. This assessment cannot be done without first obtaining a basic understanding of how biofuels affect the relationship between fuel properties, engine design, and combustion conditions. Combustion studies were conducted on biodiesel fuels from four feedstocks (palm oil, soybean oil, canola oil, and coconut oil) with two injection systems, mechanical and electronic. For the electronic system, fuel injection timing was adjusted to compensate for physical changes caused by different fuels. The emissions of nitrogen oxides (NOx) and partial combustion products were compared across both engine injection systems. The analysis showed differences in NOx emissions based on hydrocarbon chain length and degree of fuel unsaturation, with little to no NOx increase compared with ultra-low sulfur diesel fuel for most conditions. Adjusting the fuel injection timing provided some improvement in biodiesel emissions for NOx and particulate matter, particularly at lower engine loads. The results indicated that the introduction of biodiesel and biodiesel blends could have widely dissimilar effects in different types of vehicle fleets, depending on typical engine design, age, and the feedstock used for biofuel production

Common infections and neuroimaging markers of dementia in three UK cohort studies

INTRODUCTION: We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies. METHODS: We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and outcomes using linear regression, including adjustments for total intracranial volume and scanner/clinic information (basic model), age, sex, ethnicity, education, socioeconomic position, alcohol, body mass index, and smoking (fully adjusted model). Interactions between serology measures and apolipoprotein E (APOE) genotype were tested. Findings were meta-analyzed across cohorts (Nmain  = 2632; NAPOE-interaction  = 1810). RESULTS: Seropositivity to John Cunningham virus associated with smaller brain volumes in basic models (β = -3.89 mL [-5.81, -1.97], Padjusted  < 0.05); these were largely attenuated in fully adjusted models (β = -1.59 mL [-3.55, 0.36], P = 0.11). No other relationships were robust to multiple testing corrections and sensitivity analyses, but several suggestive associations were observed. DISCUSSION: We did not find clear evidence for relationships between common infections and markers of dementia risk. Some suggestive findings warrant testing for replication

A genome-wide association study of the frailty index highlights brain pathways in ageing

Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60–70 years) and Swedish TwinGene participants (n = 10,616, 41–87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p < 5*10−8). Many FI-associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on pathways in the brain