Alternative titles; symbols
Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:148,000,001-156,040,895
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | [?Homosexuality, male] | 306995 | X-linked | 2 |
Bailey and Pillard (1991) studied the genetics of homosexuality by recruiting homosexual male probands with monozygotic cotwins, dizygotic cotwins, or adoptive brothers. They found that of the relatives, 52% (29/56) of monozygotic cotwins, 22% (12/54) of dizygotic cotwins, and 11% (6/57) of adoptive brothers were homosexual. Heritability of homosexuality was considered to be substantial under a wide range of assumptions about the population base rate of homosexuality and ascertainment bias. However, the rate of homosexuality among nontwin biologic sibs, as reported by probands, 9.2% (13/142), was significantly lower than would be predicted by a simple genetic hypothesis and by other published reports. From the rates of homosexuality observed in monozygotic and dizygotic twins, ordinary sibs, and adoptive (adopted in) brothers and sisters of homosexual men (Pillard and Weinrich, 1986; Bailey and Pillard, 1991) and women (Bailey and Benishay, 1993; Bailey et al., 1993), overall heritabilities of 31 to 74% for males and 27 to 76% for females were estimated. The observation that male homosexuals usually have more gay brothers than gay sisters, whereas lesbians have more gay sisters than gay brothers, suggested that the factors responsible for familial aggregation are at least partially distinct in men compared to women.
LeVay (1991) measured the volume of 4 cell groups in the anterior hypothalamus of the brain in postmortem tissue from 3 subject groups: women, men who were presumed to be heterosexual, and homosexual men. As had been reported previously, the interstitial nucleus of the anterior hypothalamus 3 (INAH-3) was more than twice as large in the heterosexual men as in the women. It was also found by LeVay (1991) to be more than twice as large in the heterosexual men as in the homosexual men. This suggested that sexual orientation has a biologic substrate. Neuroanatomical studies have also demonstrated differences between heterosexual and homosexual men in the structure of the anterior commissure (Allen and Gorski, 1992) and the suprachiasmatic nucleus (Swaab and Hofman, 1990).
Hamer et al. (1993) performed pedigree and linkage analyses of 110 families of homosexual men. Increased rates of same-sex orientation were found in the maternal uncles and maternal male cousins of these subjects, but not in their fathers or paternal relatives, suggesting X-linked transmission. Linkage analysis using DNA markers in a selected group of 40 families in which there were 2 gay brothers and no indication of nonmaternal transmission demonstrated a correlation between homosexual orientation and the inheritance of polymorphic markers on the X chromosome in approximately 64% of the sib-pairs tested. The linkage to markers on Xq28 had a multipoint lod score of 4.0, indicating a statistical confidence level of more than 99% that at least 1 subtype of male sexual orientation is genetically influenced. In these studies, sexual orientation was assessed by the Kinsey scales, which ranged from zero for exclusive heterosexuality to 6 for exclusive homosexuality. Risch et al. (1993) provided a critique of the Hamer study. They pointed out that a priori one would expect the role of a major gene in male homosexual orientation to be limited because of the strong selective pressures against such a gene. It is unlikely that a major gene underlying such a common trait could persist over time without an extraordinary counterbalancing mechanism. They also commented that many of the limitations in the data are a reflection of the difficulties in conducting studies with so many political and social ramifications.
Hamer (1994) emphasized that the findings of his study should not be interpreted as 'medicalizing' homosexuality. Sexual preference should be viewed, he insisted, as a behavioral variable, and the studies he and others have reported as studies of the genetic influence.
Hu et al. (1995) extended their analysis of the role of Xq28 in sexual orientation by DNA linkage analyses of 2 newly ascertained series of families that contained either 2 gay brothers or 2 lesbian sisters as well as heterosexual sibs. Linkage between the Xq28 markers and sexual orientation was detected for the gay male families, but not for the lesbian families or for families that failed to meet defined inclusion criteria for the study of X-linked sexual orientation. The authors suggested that the results further support the conclusion that the Xq28 region contains a locus that influences individual variations in sexual orientation in men but not in women.
Rice et al. (1999) studied the sharing of alleles at position Xq28 in 52 gay male sib pairs from Canadian families. Four markers at Xq28 were analyzed (DXS1113; BGN, 301870; factor VIII, 300841; and DXS1108). Allele and haplotype sharing for these markers was not increased over expectation. These results do not support an X-linked gene underlying male homosexuality.
Blanchard and Klassen (1997) observed that sexual orientation in males correlated with the number of older brothers, with each additional older brother increasing the odds of homosexuality by 33%. The authors hypothesized that this fraternal birth order effect reflects progressive immunization of some mothers to the Y-linked minor histocompatibility antigen H-Y (see 426000) by each succeeding male fetus, and the concomitantly increasing effects of H-Y antibodies on the sexual differentiation of the brain in each succeeding male fetus.
From a written survey of 98 homosexual and 100 heterosexual males in northern Italy, Camperio-Ciani et al. (2004) found that female maternal relatives of homosexuals had higher fecundity compared to female maternal relatives of heterosexuals. The difference was not found in female paternal relatives, suggesting involvement of a locus on the X chromosome. In addition, homosexuals had more homosexual relatives on the maternal side compared to the paternal side; families of heterosexuals did not share this feature. Finally, the authors found that homosexual males were more often later-born than first-born and that homosexual males had more older brothers than older sisters. The last finding was consistent with the fraternal birth order effect hypothesis suggested by Blanchard and Klassen (1997). Camperio-Ciani et al. (2004) estimated that the number of homosexual males in the maternal line accounted for approximately 14% of variance in sexual orientation, whereas the number of older male brothers accounted for about 6.7% of the residual variance. The authors emphasized that about 80% of the variance remained unaccounted for by these factors.
Mustanski et al. (2005) presented the first report of a genomewide scan of sexual orientation in men. Four hundred and fifty-six individuals from 146 families (73 previously reported and 73 new) with 2 or more gay brothers were studied. Because of the previous suggestion of maternal loading of transmission of sexual orientation, which could indicate epigenetic factors acting on autosomal genes, maximum likelihood estimations (mlod) scores were calculated separately for maternal, paternal, and combined transmission. The highest mlod score was 3.45 at a position near D7S798 in 7q36 with approximately equal maternal and paternal contributions. The second highest mlod score of 1.96 was located near D8S505 in 8p12, again with equal maternal and paternal contributions. A maternal origin effect was found near marker D10S217 in 10q26, with a mlod score of 1.81 for maternal meioses and no paternal contribution. In the full sample, Mustanski et al. (2005) found no linkage to Xq28 (mlod = 0.35). In supplemental analyses, Mustanski et al. (2005) analyzed combined data from the 73 previously reported families (Hamer et al., 1993; Hu et al., 1995) and found a mlod of 6.47. They then analyzed the previously reported families using the markers from their current study and obtained a mlod of 1.99. Mustanski et al. (2005) suggested that the difference in mlod score between the restricted sample with the old and new markers was attributable to the nonoptimal position and density of the new markers.
Bocklandt et al. (2006) found that the number of women with extreme skewing of X inactivation (greater than 90%) was significantly higher among mothers of homosexual men (13 of 97 mothers; 13%) compared to mothers without homosexual sons (4 of 103 mothers; 4%). The findings were stronger for mothers with 2 or more homosexual sons (10 of 44 mothers; 23%). Bocklandt et al. (2006) suggested that the X chromosome plays a role in regulating male sexual orientation, and noted that allelic differences in the X inactivation center (see 314670) may cause primary nonrandom X inactivation.
Allen, L. S., Gorski, R. A. Sexual orientation and the size of the anterior commissure in the human brain. Proc. Nat. Acad. Sci. 89: 7199-7202, 1992. [PubMed: 1496013] [Full Text: https://doi.org/10.1073/pnas.89.15.7199]
Bailey, J. M., Benishay, D. S. Familial aggregation of female sexual orientation. Am. J. Psychiat. 150: 272-277, 1993. [PubMed: 8422079] [Full Text: https://doi.org/10.1176/ajp.150.2.272]
Bailey, J. M., Pillard, R. C. A genetic study of male sexual orientation. Arch. Gen. Psychiat. 48: 1089-1096, 1991. [PubMed: 1845227] [Full Text: https://doi.org/10.1001/archpsyc.1991.01810360053008]
Bailey, J. M., Pillard, R. C., Neale, M. C., Agyei, Y. Heritable factors influence sexual orientation in women. Arch. Gen. Psychiat. 50: 217-223, 1993. [PubMed: 8439243] [Full Text: https://doi.org/10.1001/archpsyc.1993.01820150067007]
Blanchard, R., Klassen, P. H-Y antigen and homosexuality in men. J. Theor. Biol. 185: 373-378, 1997. [PubMed: 9156085] [Full Text: https://doi.org/10.1006/jtbi.1996.0315]
Bocklandt, S., Horvath, S., Vilain, E., Hamer, D. H. Extreme skewing of X chromosome inactivation in mothers of homosexual men. Hum. Genet. 118: 691-694, 2006. [PubMed: 16369763] [Full Text: https://doi.org/10.1007/s00439-005-0119-4]
Camperio-Ciani, A., Corna, F., Capiluppi, C. Evidence for maternally inherited factors favouring male homosexuality and promoting female fecundity. Proc. Biol. Sci. 271: 2217-2221, 2004. [PubMed: 15539346] [Full Text: https://doi.org/10.1098/rspb.2004.2872]
Hamer, D. H. Personal Communication. Bethesda, Md. 9/1994.
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Hu, S., Pattatucci, A. M. L., Patterson, C., Li, L., Fulker, D. W., Cherny, S. S., Kruglyak, L., Hamer, D. H. Linkage between sexual orientation and chromosome Xq28 in males but not in females. Nature Genet. 11: 248-256, 1995. [PubMed: 7581447] [Full Text: https://doi.org/10.1038/ng1195-248]
LeVay, S. A difference in hypothalamic structure between heterosexual and homosexual men. Science 253: 1034-1037, 1991. [PubMed: 1887219] [Full Text: https://doi.org/10.1126/science.1887219]
Mustanski, B. S., DuPree, M. G., Nievergelt, C. M., Bocklandt, S., Schork, N. J., Hamer, D. H. A genomewide scan of male sexual orientation. Hum. Genet. 116: 272-278, 2005. [PubMed: 15645181] [Full Text: https://doi.org/10.1007/s00439-004-1241-4]
Pillard, R. C., Weinrich, J. D. Evidence of familial nature of male homosexuality. Arch. Gen. Psychiat. 43: 808-812, 1986. [PubMed: 3729676] [Full Text: https://doi.org/10.1001/archpsyc.1986.01800080094012]
Rice, G., Anderson, C., Risch, N., Ebers, G. Male homosexuality: absence of linkage to microsatellite markers at Xq28. Science 284: 665-667, 1999. [PubMed: 10213693] [Full Text: https://doi.org/10.1126/science.284.5414.665]
Risch, N., Squires-Wheeler, E., Keats, B. J. B. Male sexual orientation and genetic evidence. (Letter) Science 262: 2063-2065, 1993. [PubMed: 8266107] [Full Text: https://doi.org/10.1126/science.8266107]
Swaab, D. F., Hofman, M. A. An enlarged suprachiasmatic nucleus in homosexual men. Brain Res. 537: 141-148, 1990. [PubMed: 2085769] [Full Text: https://doi.org/10.1016/0006-8993(90)90350-k]