title: Inference of the genetic architecture underlying BMI and height with the use of 20,240 sibling pairs.
abstract: 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 × 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 × 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.
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; The University of Queensland, Queensland Brain Institute, Brisbane, QLD 4027, Australia.
authors.forename: Gibran
authors.initials: G
authors.lastname: Hemani
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Anna
authors.initials: A
authors.lastname: Vinkhuyzen
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Powell
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.forename: Jouke-Jan
authors.initials: JJ
authors.lastname: Hottenga
authors.forename: Abdel
authors.initials: A
authors.lastname: Abdellaoui
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Medland
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Madden
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.forename: Eco J C
authors.initials: EJ
authors.lastname: de Geus
authors.forename: Patrik K E
authors.initials: PK
authors.lastname: Magnusson
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Pedersen
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
mesh_terms: D000483:Alleles; D001827:Body Height / Q000235:genetics*; D015992:Body Mass Index; D005260:Female; D008040:Genetic Linkage; D005828:Genetics, Population; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D035781:Siblings