A Genome Wide Linkage Scan for Dizygotic Twinning in 525 Families of Mothers of Dizygotic Twins

Overview

Journal Hum Reprod

Publisher Oxford University Press

Specialty Reproductive Medicine

Date 2010 Apr 10

PMID 20378614

Citations 13

Authors

Jodie N Painter

Gonneke Willemsen

Dale Nyholt

Chantal Hoekstra

David L Duffy

Anjali K Henders

Leanne Wallace

Sue Healey

Lisa A Cannon-Albright

Mark Skolnick

Nicholas G Martin

Dorret I Boomsma

Grant W Montgomery

Affiliations

Soon will be listed here.

Abstract

Background: The tendency to conceive dizygotic (DZ) twins is a complex trait influenced by genetic and environmental factors. To search for new candidate loci for twinning, we conducted a genome-wide linkage scan in 525 families using microsatellite and single nucleotide polymorphism marker panels.

Methods And Results: Non-parametric linkage analyses, including 523 families containing a total of 1115 mothers of DZ twins (MODZT) from Australia and New Zealand (ANZ) and The Netherlands (NL), produced four linkage peaks above the threshold for suggestive linkage, including a highly suggestive peak at the extreme telomeric end of chromosome 6 with an exponential logarithm of odds [(exp)LOD] score of 2.813 (P = 0.0002). Since the DZ twinning rate increases steeply with maternal age independent of genetic effects, we also investigated linkage including only families where at least one MODZT gave birth to her first set of twins before the age of 30. These analyses produced a maximum expLOD score of 2.718 (P = 0.0002), largely due to linkage signal from the ANZ cohort, however, ordered subset analyses indicated this result is most likely a chance finding in the combined dataset. Linkage analyses were also performed for two large DZ twinning families from the USA, one of which produced a peak on chromosome 2 in the region of two potential candidate genes. Sequencing of FSHR and FIGLA, along with INHBB in MODZTs from two large NL families with family specific linkage peaks directly over this gene, revealed a potentially functional variant in the 5' untranslated region of FSHR that segregated with the DZ twinning phenotype in the Utah family.

Conclusion: Our data provide further evidence for complex inheritance of familial DZ twinning.

Citing Articles

A gene-culture co-evolutionary perspective on the puzzle of human twinship.

Dalla Ragione A, Ross C, Redhead D Evol Hum Sci. 2024; 6:e47.

PMID: 39600623 PMC: 11588562. DOI: 10.1017/ehs.2024.30.

Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.

Mbarek H, Gordon S, Duffy D, Hubers N, Mortlock S, Beck J Hum Reprod. 2023; 39(1):240-257.

PMID: 38052102 PMC: 10767824. DOI: 10.1093/humrep/dead247.

Mothers with higher twinning propensity had lower fertility in pre-industrial Europe.

Rickard I, Vullioud C, Rousset F, Postma E, Helle S, Lummaa V Nat Commun. 2022; 13(1):2886.

PMID: 35610216 PMC: 9130277. DOI: 10.1038/s41467-022-30366-9.

Genome Divergence and Dynamics in the Thin-Tailed Desert Sheep From Sudan.

Abied A, Ahbara A, Berihulay H, Xu L, Islam R, El-Hag F Front Genet. 2021; 12:659507.

PMID: 34349777 PMC: 8327097. DOI: 10.3389/fgene.2021.659507.

A major QTL at the LHCGR/FSHR locus for multiple birth in Holstein cattle.

Widmer S, Seefried F, von Rohr P, Hafliger I, Spengeler M, Drogemuller C Genet Sel Evol. 2021; 53(1):57.

PMID: 34217202 PMC: 8255007. DOI: 10.1186/s12711-021-00650-1.

References

Miller S, Dykes D, Polesky H . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988; 16(3):1215. PMC: 334765. DOI: 10.1093/nar/16.3.1215. View

Sobel E, Lange K . Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet. 1996; 58(6):1323-37. PMC: 1915074. View

Abecasis G, Cherny S, Cookson W, Cardon L . GRR: graphical representation of relationship errors. Bioinformatics. 2001; 17(8):742-3. DOI: 10.1093/bioinformatics/17.8.742. View

Sullivan P, Montgomery G, Hottenga J, Wray N, Boomsma D, Martin N . Empirical evaluation of the genetic similarity of samples from twin registries in Australia and the Netherlands using 359 STRP markers. Twin Res Hum Genet. 2006; 9(4):600-2. DOI: 10.1375/183242706778025026. View

Wiltshire S, Cardon L, McCarthy M . Evaluating the results of genomewide linkage scans of complex traits by locus counting. Am J Hum Genet. 2002; 71(5):1175-82. PMC: 385093. DOI: 10.1086/342976. View

Moore R, Erickson G, Shimasaki S . Are BMP-15 and GDF-9 primary determinants of ovulation quota in mammals?. Trends Endocrinol Metab. 2004; 15(8):356-61. DOI: 10.1016/j.tem.2004.08.008. View

Beemsterboer S, Homburg R, Gorter N, Schats R, Hompes P, Lambalk C . The paradox of declining fertility but increasing twinning rates with advancing maternal age. Hum Reprod. 2006; 21(6):1531-2. DOI: 10.1093/humrep/del009. View

Holliday E, Mowry B, Nyholt D . A reanalysis of 409 European-Ancestry and African American schizophrenia pedigrees reveals significant linkage to 8p23.3 with evidence of locus heterogeneity. Am J Med Genet B Neuropsychiatr Genet. 2008; 147B(7):1080-8. DOI: 10.1002/ajmg.b.30722. View

Boomsma D, Vink J, van Beijsterveldt T, de Geus E, Beem A, Mulder E . Netherlands Twin Register: a focus on longitudinal research. Twin Res. 2003; 5(5):401-6. DOI: 10.1375/136905202320906174. View

10.

Busjahn A, Knoblauch H, Faulhaber H, Aydin A, UHLMANN R, Tuomilehto J . A region on chromosome 3 is linked to dizygotic twinning. Nat Genet. 2000; 26(4):398-9. DOI: 10.1038/82515. View

11.

Lewis C, Healey S, Martin N . Genetic contribution to DZ twinning. Am J Med Genet. 1996; 61(3):237-46. DOI: 10.1002/(SICI)1096-8628(19960122)61:3<237::AID-AJMG7>3.0.CO;2-R. View

12.

Bodensteiner K, Clay C, Moeller C, Sawyer H . Molecular cloning of the ovine Growth/Differentiation factor-9 gene and expression of growth/differentiation factor-9 in ovine and bovine ovaries. Biol Reprod. 1999; 60(2):381-6. DOI: 10.1095/biolreprod60.2.381. View

13.

McGrath S, Esquela A, Lee S . Oocyte-specific expression of growth/differentiation factor-9. Mol Endocrinol. 1995; 9(1):131-6. DOI: 10.1210/mend.9.1.7760846. View

14.

Hoekstra C, Zhao Z, Lambalk C, Willemsen G, Martin N, Boomsma D . Dizygotic twinning. Hum Reprod Update. 2007; 14(1):37-47. DOI: 10.1093/humupd/dmm036. View

15.

Marcus K, Sweep C, van der Burgt I, Noordam C . Impaired Sertoli cell function in males diagnosed with Noonan syndrome. J Pediatr Endocrinol Metab. 2009; 21(11):1079-84. DOI: 10.1515/jpem.2008.21.11.1079. View

16.

Rozen S, Skaletsky H . Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol. 1999; 132:365-86. DOI: 10.1385/1-59259-192-2:365. View

17.

Pharoah P, Antoniou A, Bobrow M, Zimmern R, Easton D, Ponder B . Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet. 2002; 31(1):33-6. DOI: 10.1038/ng853. View

18.

Hanrahan J, Gregan S, Mulsant P, Mullen M, Davis G, Powell R . Mutations in the genes for oocyte-derived growth factors GDF9 and BMP15 are associated with both increased ovulation rate and sterility in Cambridge and Belclare sheep (Ovis aries). Biol Reprod. 2003; 70(4):900-9. DOI: 10.1095/biolreprod.103.023093. View

19.

Wunsch A, Ahda Y, Banaz-Yasar F, Sonntag B, Nieschlag E, Simoni M . Single-nucleotide polymorphisms in the promoter region influence the expression of the human follicle-stimulating hormone receptor. Fertil Steril. 2005; 84(2):446-53. DOI: 10.1016/j.fertnstert.2005.02.031. View

20.

Meulemans W, Lewis C, Boomsma D, Derom C, Van Den Berghe H, Orlebeke J . Genetic modelling of dizygotic twinning in pedigrees of spontaneous dizygotic twins. Am J Med Genet. 1996; 61(3):258-63. DOI: 10.1002/(SICI)1096-8628(19960122)61:3<258::AID-AJMG10>3.0.CO;2-S. View