Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated approximately 2,000, approximately 3,700 and approximately 9,500 SNPs explained approximately 21%, approximately 24% and approximately 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Inference of the genetic architecture underlying BMI and height with the use of 20,240 sibling pairs

Evidence that complex traits are highly polygenic has been presented by population-based genome-wide association studies (GWASs) through the identification of many significant variants, as well as by family-based de novo sequencing studies indicating that several traits have a large mutational target size. Here, using a third study design, we show results consistent with extreme polygenicity for body mass index (BMI) and height. On a sample of 20,240 siblings (from 9,570 nuclear families), we used a within-family method to obtain narrow-sense heritability estimates of 0.42 (SE = 0.17, p = 0.01) and 0.69 (SE = 0.14, p = 6 x 10(-)(7)) for BMI and height, respectively, after adjusting for covariates. The genomic inflation factors from locus-specific linkage analysis were 1.69 (SE = 0.21, p = 0.04) for BMI and 2.18 (SE = 0.21, p = 2 x 10(-10)) for height. This inflation is free of confounding and congruent with polygenicity, consistent with observations of ever-increasing genomic-inflation factors from GWASs with large sample sizes, implying that those signals are due to true genetic signals across the genome rather than population stratification. We also demonstrate that the distribution of the observed test statistics is consistent with both rare and common variants underlying a polygenic architecture and that previous reports of linkage signals in complex traits are probably a consequence of polygenic architecture rather than the segregation of variants with large effects. The convergent empirical evidence from GWASs, de novo studies, and within-family segregation implies that family-based sequencing studies for complex traits require very large sample sizes because the effects of causal variants are small on average.

Marker development for genes controlling mango tree architecture

Identification of candidate genes controlling, mango tree architecture.

Exterior view of expressionist painter Emil Luethy's home; Gotthardstr. 41 (Basel?) Architecture Residences Exterior

Handwritten on verso: zu obest mein Atelier (My studio on the top floor)

Rudolf and Antoinette von Kahler in living room; Vienna-Doebling Architecture; Residences

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Albert Einstein's Weekend Home; Caputh, near Berlin Architecture; Residences; Exterior

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Deck; Albert Einstein's Weekend Home; Caputh, near Berlin Architecture; Residences; Exterior

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Study; Albert Einstein's Weekend Home; Caputh, near Berlin Architecture; Residences; Interior

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Staircase; Albert Einstein's Weekend Home; Caputh, near Berlin Architecture; Residences; Interior

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Albert Einstein's Weekend Home; Caputh, near Berlin Architecture; Residences; Exterior

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Deck; Albert Einstein's Weekend Home; Caputh, near Berlin Architecture; Residences; Exterior

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View from Deck; Albert Einstein's Weekend Home; Caputh, near Berlin Architecture; Residences; Exterior

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Elsa Einstein with unidentified woman sitting on the porch of Albert Einstein's Weekend Home; Caputh, near Berlin Architecture; Residences; Exterior

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Gottschalk residence; Zeppelinstrasse 2, Hannover, Germany. architecture residences

Verso: Possibly the Gottschalk house at Zeppelinstrasse 2 in Hannover, Germany, dated 1911. Removed from an unknown scrapbook.