Dizygotic twinning is not linked to variation at the alpha-inhibin locus on human chromosome 2

Natural multiple pregnancy in women leading to dizygotic (DZ) twins is fami lial and varies across racial groups, suggesting a genetic predisposition. Mothers of DZ twins have a higher incidence of spontaneous multiple ovulati on and elevated FSH concentrations. FSH release is controlled by feedback o f inhibin peptides from the ovary, and immunization against inhibin alpha-s ubunit results in an increased ovulation rate in animals. The inhibin alpha -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 alpha-inhibin l ocus mapped within 3 centimorgans of D2S164, and Linkage with DZ twinning w as excluded [decimal log odds ratio (LOD) score, -2.81 at theta = 0]. There was complete exclusion of linkage (LOD, less than -2) of a gene conferring relative risk 1.8 (lambda 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) acr oss chromosome 2. We conclude that dizygotic twinning is not linked to vari ation in the alpha-inhibin locus. The results also suggest that mutations i n other candidates on chromosome 2, including the receptor for FSH and the beta(B)-inhibin subunit (INHBB) cannot be major contributors to risk for DZ twinning.