Older Brothers and Male Homosexuality: Antibodies as an Explanation

The familial nature of homosexuality in men has been known for decades. ¹ The finding is gender-specific; homosexual men have a higher proportion of homosexual brothers than heterosexual men, but not a higher proportion of homosexual sisters. ²

It has also been known for decades that homosexual men have a lower birth order, on average, than heterosexual men.^{3, 4} More specifically, homosexual men have a greater number of older brothers but not older sisters, younger brothers, or younger sisters. ⁵

The evidence for the fraternal birth order effect is strong. There is a very large number of studies on the subject, and these studies have been subjected to meta-analysis. In this meta-analysis, ⁶ the strength of the effect in persons from small versus large families and in homosexual males with masculine gender identities versus those with feminine gender identities were compared.

The meta-analysis included 30 homosexual and 30 heterosexual groups from 26 studies. The pooled sample included 7140 homosexual and 12,837 heterosexual males. The outcome variable of interest, the older brothers odds ratio (OR), was calculated as follows:

First, an older brothers ratio was calculated for homosexuals and heterosexuals separately. This value was the number of older brothers divided by the number of all other siblings.

Important findings from the meta-analysis are presented in Box 1. In summary, the meta-analysis found that having a larger number of older brothers was associated with a significantly increased risk of homosexual orientation, especially feminine or transgender homosexual orientation. This fraternal birth order effect was unrelated to family size. Of interest, the meta-analysis also found that only about 15% to 29% of men in any given homosexual group could attribute their sexual orientation to the fraternal birth order effect.

Why should having (more) older brothers increase the risk of homosexuality in men? A superficially plausible explanation is that fraternal sexual exposure or experimentation in childhood may behaviorally prime individuals towards a homosexual orientation. This explanation fails because it does not explain why having younger brothers does not predispose to male homosexuality or why the same-sex sibling effect does not exist for women.

The fraternal birth order effect has therefore led to a search for biological explanations, and an in utero maternal immune response has been suggested.^{7, 8} In this context, Bogaert et al. ⁹ examined plasma from mothers of male offspring about half of whom had a gay son, and controls, comprising men as well as women with no sons. They used immune assays to study whether mothers develop antibodies against two Y-linked proteins that are important in male brain development in utero, and whether this effect strengthens with succeeding male gestations. The proteins that they studied were protocadherin 11 Y-linked (PCDH11Y) and neuroligin 4 Y-linked (NLGN4Y; isoforms 1 and 2).

Important findings from the study of Bogaert et al. ⁹ are presented in Box 2. In summary, the findings suggested that the maternal immune response against a Y-linked protein (that is important in male brain development in utero) is associated with homosexual orientation in sons. This protein, the NLGN4Y protein, is a cell-adhesion protein that plays a vital role in cell-cell interactions, specifically in the process of synapse formation, during in utero neurodevelopment. ⁷

At the risk of stating the obvious, it must be noted that the development of sexual orientation is multifactorial and depends on biological and social influences from the womb through early life. Nevertheless, if an antibody response can be confirmed as an etiological factor, might primary prevention interventions be possible?

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Table 1.

Important Findings from the Meta-analysis of Blanchard et al. ⁶ : Fraternal Birth Order Effect in Homosexual Males

1. The mean older brothers ratio was 0.50 versus 0.32 in homosexuals versus heterosexuals, respectively.

2. There was consistent evidence for the fraternal birth order effect. The older brothers OR was significantly > 1 in 20 groups and nonsignificantly < 1 in one group. It was nonsignificantly > 1 in the remaining 9 groups.

3. The pooled older brothers OR was 1.47 (95% CI, 1.33-1.62). There was substantial heterogeneity.

4. In subgroup analyses, the magnitude of the fraternal birth order effect was significantly greater in the 12 feminine or transgender homosexual groups than in the other 18 homosexual groups. In this context, masculine, feminine, and transgender were defined by reported feelings and behavior.

5. The fraternal birth order effect did not vary significantly in relation to family size.

Abbreviation: OR = odds ratio.

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Table 2.

Important Findings from the Study of Bogaert et al. ⁹ : Antibodies in Mothers of Gay Men

1. Anti-NLGN4Y antibody levels were higher in women than in men.

2. After controlling for number of pregnancies, mothers of gay sons, especially those with older brothers, had higher anti-NLGN4Y antibody levels than control women, including mothers of heterosexual sons.