Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Ursula Schlosstein nee Gottschalk teaching children art at Allen's Lane Art Center which she founded; Philadelphia, Pennsylvania.

Ursula Schlosstein born Gottschalk in her nursery school, Allens Lane Art Center.

Ursula Schlosstein nee Gottschalk teaching children art at Allen's Lane Art Center which she founded; Philadelphia, Pennsylvania.

Ursula Schlosstein born Gottschalk in her nursery school, Allens Lane Art Center.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

O bruxo e o ilusionista: Machado de Assis e seu leitor Woddy Allen

A presente tese tem como intuito investigar as relações entre as narrativas de Machado de Assis e de Woody Allen, autores de épocas e culturas bastante distintas. No entanto, através da análise do papel da ironia na obra de ambos tornou-se possível aproximar Memórias póstumas de Brás Cubas, romance de 1881 de Machado, e Stardust Memories, filme lançado em 1980 pelo diretor Woody Allen. A investigação divide-se em três etapas. No primeiro capítulo, analisa-se a aproximação entre os dois autores através de uma mesma visão sobre a ficção presente tanto na obra de Machado quanto na de Allen. Esta visão encontra-se fundamentada através de uma tradição literária burlesca que rompe com o primado realista na narrativa ficcional. No segundo capítulo, procura-se demonstrar como a perspectiva não realista escapa a uma regra moralizante na ficção, para valorizar uma postura ética, isto é, para se definir o ethos da narrativa. A ironia, assim, será a morada da ficção de ambos os autores, que problematizam o mundo incluindo nele a própria narrativa. E no terceiro e último capítulo, analisa-se a relação ficcional nas duas obras com a memória. A memória, elemento constituinte da identidade humana, revela-se uma linguagem própria e opressora aos narradores memorialistas, impondo-lhes a inexorabilidade do tempo. Dessa forma, suas ficções seriam uma luta incessante do homem contra o seu caminhar para a morte

对Allen的时间理论的某些改进

Ａｌｌｅｎ的时间理论因直观、易懂而倍受推崇，但它存在不能处理连续变化事件等缺欠。本文提出更为一般的时间理论框架，以扩展Ａｌｌｅｎ的理论，本框架的特点为：（ｌ）将Ａｌｌｅｎ的理论纳入其中；（２）可由时间点构造时区，并可处理时区和时间点；（３）以时间元素集的２Ｄ图形表示为基础的约束传播算法，既高效又可视化。

Discourses Commemorative of Professor Tayler Lewis and Professor Isaac W. Jackson

Discourses

Missionary survey as an aid to intelligent co-operation in foreign missions, by Roland Allen, and Thomas Cochrane.

http://www.archive.org/details/missionarysurvey13360gut

Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy.

The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1-NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are "ciliopathies". Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.

Ventricular conduction and long-term heart failure outcomes and mortality in African Americans: insights from the Jackson Heart Study.

BACKGROUND: QRS prolongation is associated with adverse outcomes in mostly white populations, but its clinical significance is not well established for other groups. We investigated the association between QRS duration and mortality in African Americans. METHODS AND RESULTS: We analyzed data from 5146 African Americans in the Jackson Heart Study stratified by QRS duration on baseline 12-lead ECG. We defined QRS prolongation as QRS≥100 ms. We assessed the association between QRS duration and all-cause mortality using Cox proportional hazards models and reported the cumulative incidence of heart failure hospitalization. We identified factors associated with the development of QRS prolongation in patients with normal baseline QRS. At baseline, 30% (n=1528) of participants had QRS prolongation. The cumulative incidences of mortality and heart failure hospitalization were greater with versus without baseline QRS prolongation: 12.6% (95% confidence interval [CI], 11.0-14.4) versus 7.1% (95% CI, 6.3-8.0) and 8.2% (95% CI, 6.9-9.7) versus 4.4% (95% CI, 3.7-5.1), respectively. After risk adjustment, QRS prolongation was associated with increased mortality (hazard ratio, 1.27; 95% CI, 1.03-1.56; P=0.02). There was a linear relationship between QRS duration and mortality (hazard ratio per 10 ms increase, 1.06; 95% CI, 1.01-1.12). Older age, male sex, prior myocardial infarction, lower ejection fraction, left ventricular hypertrophy, and left ventricular dilatation were associated with the development of QRS prolongation. CONCLUSIONS: QRS prolongation in African Americans was associated with increased mortality and heart failure hospitalization. Factors associated with developing QRS prolongation included age, male sex, prior myocardial infarction, and left ventricular structural abnormalities.