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.

Henry Marx shining shoes to earn money for his family; Washington Heights, New York Portraits Children

Henry Marx was born in Michelstadt/Hessen and emigrated to New York with his family in early 1937 when he was nine years old. He went to school but also delivered newspapers and shined shoes to help his family financially as his father only worked whatever odd jobs he could during the war years. Going from store to store shining shoes on weekends was Henry's main source of income. He had to wake up early in order to reserve the spot shown in this photograph, competing with a father and two sons who traveled from Brooklyn to Washington Heights to shine shoes.

Exterior view of the Boehm family hat factory; Novy Jicin, Czech Republic Businesses

Tovarna na Klobouky Fv. Boehm

Erich Gustav Baum in the drivers seat of a car with his wife Grete nee Dublon and their daughter Ilse Baum in the back seat Portraits Family

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Ilse Baum's class portrait Portraits Family

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View of Muensterstrasse including Erich Gustav Baum's haberdashery store (Waesche Baum); Rheine i.W. Portraits Family

The shop was shut down by the Nazis several times during the 1930s

Grete Baum nee Dublon assisting a customer in her husband Erich Gustav Baum's haberdashery store (Waesche Baum); Muensterstrasse, Rheine i.W. Portraits Family

The shop was shut down by the Nazis several times during the 1930s

Portrait of the six Baum family siblings Portraits Family

Standing are Fritz, Joseph and Lilly. The youngest is Hans. Erich is seated center and Walter is seated on the far right.

Fanny and Hugo Eichenwald with two of their three children, Fritz and Hanne outside of their home; Rheine Portraits; Family

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The three Eichenwald children, Fritz, Hanne and Hans Portraits; Family

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Isidor Simon seated at an outdoor table with his wife Friederike nee Falkenburg and two grandchildren, Helmuth and Walther Simon Portraits Family

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Loci affecting gamma-glutamyl transferase in adults and adolescents show age x SNP interaction and cardiometabolic disease associations

Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 x 10(-8); rs944002 in C14orf73 on chromosome 14, P = 4.7 x 10(-13); rs340005 in RORA on chromosome 15, P = 2.4 x 10(-8)), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P(HET) = 5.6 x 10(-12) at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.