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.

Portrait of Isidor Witkowski and Caecilie Witkowski nee Seligsohn Portraits Couples

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Portrait of Moritz and Helene Leffmann Portraits Couples

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Portrait of unidentified woman Portraits Women

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Portrait of unidentified man Portraits Men

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Wedding portrait of Freddy Gottschalk and Barbara Joan Doble with guests; Welwyn Garden City, England.

Portrait includes a number of family members who were able to get to England before the war and who chose to remain there.

Kohnberger family portrait.

From left to right, back row: Ernst Schueller, Hermine Schueller, Laura Stiassny, Sigmund Stiassny, Martha Pollak, Johanna Mislap and Jacob Hermann; front row: Melanie Herrmann (or Irene Tiring), Conrad Tiring, Emilie Kohnberger and Solomon Kohnberger

Studio portraits of Rahel Bürger Apfel.

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Mathias family preparing to board the ship "Deutschland" to emigrate from Germany to New York Portraits; Family

On January 6, 1938 our family left Nazi Germany and boarded a ship "Deutschland" for New York. This ended our family's life in Germany forever. Rudolph ES Mathias.

The family Aaron Kahn /

Family history, translated by Fred Kahn.

Karl Josef Scheuermann Collection 1981-1986

Photocopies of correspondence between Scheuermann, Ernst Cramer, Cardinal Ratzinger, Reuben Hecht on Pope John XXIII and his alleged repentance prayer.

Zur Geschichte der Familie Schragenheim.

Family history

Bianca Gerstmann Portraits Women

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Bianca and Felix Gerstmann in front of the Parkhotel Richmond; Karlsbad Portraits Couples

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Bianca and Felix Gerstmann in front of a car in Kuala Lumpur ? Portraits Couples

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