Here, we study the intricate relationship between gut microbiota and host cometabolic phenotypes associated with dietary-induced impaired glucose homeostasis and nonalcoholic fatty liver disease (NAFLD) in a mouse strain (129S6) known to be susceptible to these disease traits, using plasma and urine metabotyping, achieved by ¹ H NMR spectroscopy. Multivariate statistical modeling of the spectra shows that the genetic predisposition of the 129S6 mouse to impaired glucose homeostasis and NAFLD is associated with disruptions of choline metabolism, i.e., low circulating levels of plasma phosphatidylcholine and high urinary excretion of methylamines (dimethylamine, trimethylamine, and trimethylamine- N -oxide), coprocessed by symbiotic gut microbiota and mammalian enzyme systems. Conversion of choline into methylamines by microbiota in strain 129S6 on a high-fat diet reduces the bioavailability of choline and mimics the effect of choline-deficient diets, causing NAFLD. These data also indicate that gut microbiota may play an active role in the development of insulin resistance.

Human population genomic studies, including whole‐genome sequencing, were undertaken to identify determinants of bone mineral density (BMD), a major predictor of osteoporotic fractures. Non‐coding variants with large effects on BMD and fractures were identified near the EN1 locus and mouse studies confirmed this gene has an important role in skeletal biology. Bone mineral density (BMD) is heritable and is a major predictor of osteoporotic fractures. Using whole-genome sequencing from the UK10K consortium, whole exome sequencing and deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel, this collaborative study identifies novel non-coding genetic variants with large effects on bone density in individuals of European ancestry. Notable findings include low-frequency non-coding variants near the EN1 locus — and mouse studies confirm that this gene has a role in determining bone mass. In addition, the authors observed an excess of association signals arising from deleterious coding and conserved non-coding variants. Collectively, this work suggests that low-frequency non-coding variants have large effects on BMD and fracture in the general population. The extent to which low‐frequency (minor allele frequency (MAF) between 1–5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants1,2,3,4,5,6,7,8, as well as rare, population‐specific, coding variants9. Here we identify novel non‐coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole‐genome sequencing (n = 2,882 from UK10K (ref. 10); a population‐based genome sequencing consortium), whole‐exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low‐frequency non‐coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10−14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10−11; ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low‐frequency non‐coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10−11). In general, there was an excess of association signals arising from deleterious coding and conserved non‐coding variants. These findings provide evidence that low‐frequency non‐coding variants have large effects on BMD and fracture, thereby providing rationale for whole‐genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Many aspects of physiology and behavior follow a circadian rhythm. Brain and muscle Arnt-like protein-1 (BMAL1) is a key component of the mammalian molecular clock, which controls circadian oscillations. In the rat, the gene encodingBmal1is located within hypertension susceptibility loci. We analyzed the SNP distribution pattern in a congenic interval associated with hypertension in the spontaneously hypertensive rat (SHR), and we show thatBmal1maps close to a region genetically divergent between SHR and its normotensive (Wistar–Kyoto) counterpart.Bmal1sequencing in rat strains identified 19 polymorphisms, including an SHR promoter variant that significantly affects Gata-4 activation of transcription in transient transfection experiments. A genetic association study designed to test the relevance of these findings in 1,304 individuals from 424 families primarily selected for type 2 diabetes showed that twoBMAL1haplotypes are associated with type 2 diabetes and hypertension. This comparative genetics finding translated from mouse and rat models to human provides evidence of a causative role ofBmal1variants in pathological components of the metabolic syndrome.