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Dizygotic Twinning Is Not Linked to Variation at the -Inhibin Locus on Human Chromosome 2¹

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{at}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 ß_B-inhibin subunit (INHBB) cannot be major contributors to risk for DZ twinning.

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