BackgroundMRI relaxometry mapping and proton density fat fraction (PDFF) have been proposed for the evaluation of hepatic fibrosis. However, sex-specific relationships of age and body fat with... Show moreBackgroundMRI relaxometry mapping and proton density fat fraction (PDFF) have been proposed for the evaluation of hepatic fibrosis. However, sex-specific relationships of age and body fat with these MRI parameters have not been studied in detail among adults without clinically manifest hepatic disease. We aimed to determine the sex-specific correlation of multiparametric MRI parameters with age and body fat and to evaluate their interplay associations.Methods147 study participants (84 women, mean age 48±14 years, range 19-85 years) were prospectively enrolled. 3 T MRI including T1, T2 and T1ρ mapping and PDFF and R2* map were acquired. Visceral and subcutaneous fat were measured on the fat images from Dixon water-fat separation sequence.ResultsAll MRI parameters demonstrated sex difference except for T1ρ. PDFF was more related to visceral than subcutaneous fat. Per 100 ml gain of visceral or subcutaneous fat is associated with 1 or 0.4% accretion of liver fat, respectively. PDFF and R2* were higher in men (both P = 0.01) while T1 and T2 were higher in women (both P < 0.01). R2* was positively but T1 and T2 were negatively associated with age in women (all P < 0.01), while T1ρ was positively related to age in men (P < 0.05). In all studies, R2* was positively and T1ρ was negatively associated with PDFF (both P <0.0001).ConclusionVisceral fat plays an essential role in the elevated liver fat. When using MRI parametric measures for liver disease evaluation, the interplay between these parameters should be considered. Show less
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we... Show moreGenetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. Show less
Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients... Show morePostsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes. Show less
Giri, A.; Hellwege, J.N.; Keaton, J.M.; Park, J.; Qiu, C.X.; Warren, H.R.; ... ; Million Vet Program 2019
