title: Following the footprints of polymorphic inversions on SNP data: from detection to association tests.
abstract: Inversion polymorphisms have important phenotypic and evolutionary consequences in humans. Two different methodologies have been used to infer inversions from SNP dense data, enabling the use of large cohorts for their study. One approach relies on the differences in linkage disequilibrium across breakpoints; the other one captures the internal haplotype groups that tag the inversion status of chromosomes. In this article, we assessed the convergence of the two methods in the detection of 20 human inversions that have been reported in the literature. The methods converged in four inversions including inv-8p23, for which we studied its association with low-BMI in American children. Using a novel haplotype tagging method with control on inversion ancestry, we computed the frequency of inv-8p23 in two American cohorts and observed inversion haplotype admixture. Accounting for haplotype ancestry, we found that the European inverted allele in children carries a recessive risk of underweight, validated in an independent Spanish cohort (combined: OR= 2.00, P = 0.001). While the footprints of inversions on SNP data are complex, we show that systematic analyses, such as convergence of different methods and controlling for ancestry, can reveal the contribution of inversions to the ancestral composition of populations and to the heritability of human disease.
authors: Center for Research in Environmental Epidemiology (CREAL), Doctor Aiguader 88, Barcelona 08003, Spain IMIM (Hospital del Mar Research Institute), Doctor Aiguader 88, Barcelona 08003, Spain acaceres@creal.cat.
authors: Alejandro
authors: A
authors: Cáceres
authors: Center for Research in Environmental Epidemiology (CREAL), Doctor Aiguader 88, Barcelona 08003, Spain IMIM (Hospital del Mar Research Institute), Doctor Aiguader 88, Barcelona 08003, Spain Centro de Investigacion Biomedica en Red en Epidemiologia y Salud Publica (CIBERESP), Barcelona 08036, Spain Department of Mathematics, Universitat Autonoma de Barcelona (UAB), Barcelona 08193, Spain.
authors: Juan R
authors: JR
authors: González
mesh_terms: D000465:Algorithms; D015992:Body Mass Index; D002675:Child, Preschool; D007446:Chromosome Inversion; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques / Q000379:methods*; D060148:HapMap Project; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D014481:United States