Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Nov;50(8):3377-3383.
doi: 10.1007/s10508-021-02146-x. Epub 2021 Sep 13.

Genome-Wide Linkage and Association Study of Childhood Gender Nonconformity in Males

Alan R Sanders  1   2 , Gary W Beecham  3   4 , Shengru Guo  3 , Khytam Dawood  5 , Gerulf Rieger  6 , Ritesha S Krishnappa  7 , Alana B Kolundzija  8 , J Michael Bailey  9 , Eden R Martin  3   4
Affiliations

Genome-Wide Linkage and Association Study of Childhood Gender Nonconformity in Males

Alan R Sanders et al. Arch Sex Behav. 2021 Nov.

Abstract

Male sexual orientation is influenced by environmental and complex genetic factors. Childhood gender nonconformity (CGN) is one of the strongest correlates of homosexuality with substantial familiality. We studied brothers in families with two or more homosexual brothers (409 concordant sibling pairs in 384 families, as well as their heterosexual brothers), who self-recalled their CGN. To map loci for CGN, we conducted a genome-wide linkage scan (GWLS) using SNP genotypes. The strongest linkage peaks, each with significant or suggestive two-point LOD scores and multipoint LOD score support, were on chromosomes 5q31 (maximum two-point LOD = 4.45), 6q12 (maximum two-point LOD = 3.64), 7q33 (maximum two-point LOD = 3.09), and 8q24 (maximum two-point LOD = 3.67), with the latter not overlapping with previously reported strongest linkage region for male sexual orientation on pericentromeric chromosome 8. Family-based association analyses were used to identify associated variants in the linkage regions, with a cluster of SNPs (minimum association p = 1.3 × 10-8) found at the 5q31 linkage peak. Genome-wide, clusters of multiple SNPs in the 10-6 to 10-8 p-value range were found at chromosomes 5p13, 5q31, 7q32, 8p22, and 10q23, highlighting glutamate-related genes. This is the first reported GWLS and genome-wide association study on CGN. Further increasing genetic knowledge about CGN and its relationships to male sexual orientation should help advance our understanding of the biology of these associated traits.

Keywords: Childhood gender nonconformity; Complex trait; GWAS; Genome-wide linkage scan; Male sexual orientation.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
NormCGN distributions plotted by sexual orientation. normCGN score bins (x-axis) are plotted against percentage of men (y-axis) in two panels. The top panel of 33 heterosexual men and the bottom panel of 791 homosexual men
Fig. 2
Fig. 2
Multipoint LOD scores plotted by chromosomal positions for the GWLS of normCGN. Adjacent chromosomes are separated by alternating black and gray lines. Maximum multipoint LOD scores are at ∼129 cM on chromosome 8q24
Fig. 3
Fig. 3
Manhattan plot of GWAS for normCGN. Plot of negative log10 of the p-values for the single SNP association analysis, ordered along the x-axis by chromosomal position
See this image and copyright information in PMC

References

    1. Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, McVean GA. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061–1073. doi: 10.1038/nature09534. - DOI - PMC - PubMed
    1. Abecasis GR, Cherny SS, Cookson WO, Cardon LR. Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nature Genetics. 2002;30:97–101. doi: 10.1038/ng786. - DOI - PubMed
    1. Alanko K, Santtila P, Harlaar N, Witting K, Varjonen M, Jern P, Sandnabba NK. Common genetic effects of gender atypical behavior in childhood and sexual orientation in adulthood: A study of Finnish twins. Archives of Sexual Behavior. 2010;39:81–92. doi: 10.1007/s10508-008-9457-3. - DOI - PubMed
    1. Bailey JM, Bell AP. Familiality of female and male homosexuality. Behavior Genetics. 1993;23:313–322. doi: 10.1007/BF01067431. - DOI - PubMed
    1. Bailey JM, Benishay DS. Familial aggregation of female sexual orientation. American Journal of Psychiatry. 1993;150:272–277. doi: 10.1176/ajp.150.2.272. - DOI - PubMed

Publication types

LinkOut - more resources