Dizygotic Twinning Is Not Linked to Variation at the -Inhibin Locus on Human Chromosome 21
Grant W. Montgomery, David L. Duffy, Jeff Hall, Barbara R. Haddon, Masataka Kudo, Elizabeth A. Mcgee, James S. Palmer, Aaron J. Hsueh, Dorret I. Boomsma and Nicholas G. Martin
Genetic Epidemiology Laboratory, Queensland Institute of Medical Research and Joint Genetics Program, University of Queensland (G.W.M., D.L.D., B.R.H., J.S.P., N.G.M.), Brisbane, Queensland 4029, Australia; AxyS Pharmaceuticals, Inc. (J.H.), La Jolla, California 92037; Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University Medical Center (M.K., E.A.M., A.J.H.), Stanford, California 94305-5371; and Psychology Department, Free University (D.I.B.), 1081 HV Amsterdam, The Netherlands
Address all correspondence and requests for reprints to: Dr. Grant Montgomery, Queensland Institute of Medical Research, Post Office, Royal Brisbane Hospital, Queensland 4029, Australia. E-mail: grantM@qimr.edu.au.
Natural multiple pregnancy in women leading to dizygotic (DZ) twins is familial and varies across racial groups, suggesting a genetic predisposition. Mothers of DZ twins have a higher incidence of spontaneous multiple ovulation and elevated FSH concentrations. FSH release is controlled by feedback of inhibin peptides from the ovary, and immunization against inhibin -subunit results in an increased ovulation rate in animals. The inhibin -subunit is therefore a candidate gene for mutations that may increase the frequency of DZ twinning. Restriction digests of a PCR product from exon 1 with the enzyme SpeI detects a C/T polymorphism at bp 128 with two alleles of 447 and 323/124 bp. The polymorphism was typed in 1125 individuals from 326 pedigrees with 717 mothers of spontaneous DZ twins. The -inhibin locus mapped within 3 centimorgans of D2S164, and linkage with DZ twinning was excluded [decimal log odds ratio (LOD) score, -2.81 at = 0]. There was complete exclusion of linkage (LOD, less than -2) of a gene conferring relative risk 1.8 (s, >1.8) across the chromosome, except at the p-terminus region and a small peak (maximum LOD score, 0.6) in the region of D2S151-D2S326. Analysis using either recessive or dominant models excluded linkage with DZ twinning in this population (LOD score, less than -2.5) across chromosome 2. We conclude that dizygotic twinning is not linked to variation in the -inhibin locus. The results also suggest that mutations in other candidates on chromosome 2, including the receptor for FSH and the ßB-inhibin subunit (INHBB) cannot be major contributors to risk for DZ twinning.
