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RORA: Just the Gene For Autism We Wanted!

Sex hormone gene effects explain autism’s sex ratio

Asperger noticed it from the very beginning, and today we know for sure that male autistics outnumber female ones by at least 4:1. This is especially so of high-functioning autism spectrum disorder (ASD) aptly coinciding with what we now call Asperger's syndrome.

But why? ASD is not a classical sex-linked genetic disorder similar to haemophilia or color blindness. Nevertheless, tantalizing findings have linked exposure to testosterone before birth with autistic symptoms such as deficits in eye-contact, vocabulary, and social relationships along with restricted interests at age 4. But the exact developmental mechanism involved remained completely unknown.

Now the discovery of a new candidate gene implicated in autism known as RORA (for retinoic acid-related orphan receptor-alpha) reveals what that mechanism might be and also corroborates the key claims of the imprinted brain theory. According to this theory, it is the epigenetic expression, and not just the inheritance of genes that accounts for how ASD runs in families. Additionally, it predicts that imbalances in expression in the paternal/male direction cause ASD, and imbalances in the opposite, maternal/female one cause psychotic spectrum disorders (PSD) such as schizophrenia. RORA confirms both predictions.

RORA is involved in several key processes implicated in autism, including brain cell (Purkinje) differentiation; muscle tone and development of the cerebellum; protection of neurons against chemical stress; suppression of inflammation; and regulation of circadian rhythm. In research on twins published last year, the expression of RORA was indeed shown to be affected by a key epigenetic factor (methylation). This explains, for example, how one of a pair of otherwise identical twins can be autistic but the other not. As I have pointed out before, identical twins may share the same genes, but may vary in their expression.

 PLoS ONE 6(2): 1371/journal
Source: PLoS ONE 6(2): 1371/journal

The new study has revealed more about how RORA works. As the illustration shows, testosterone--the paradigmatic male sex hormone--acts on androgen receptors (AR) to reduce RORA. Estrogen--the female hormonal counterpart only one atom different--acts on estrogen receptors (ER) to increase RORA. The figure also shows how aromatase (an enzyme responsible for the conversion of testosterone to estrogen) is a target for RORA. The authors note that both RORA and aromatase are strongly correlated in brain tissue and relatively reduced in the frontal cortex of ASD subjects--a region of the brain known to be critically involved in mentalistic cognition. They conclude that the reduction of RORA seen in autism is exacerbated by a negative feedback mechanism involving decreased aromatase level, which further causes accumulation of testosterone.

As the researchers point out, this is the first description of a candidate gene for autism that is responsive to both male and female sex hormones. However, it is also a finding that beautifully endorses the imprinted brain theory because it demonstrates how male genetic influence predisposes to ASD and how the presence of female sex hormones such as estrogen is protective, thereby explaining the sex ratio is autism.

Indeed, the mechanism involved might even explain more. The ratio of length of the index to the ring finger is believed to reflect sex hormone influences before birth. An unpublished study of finger-length ratios in 460 subjects reported by John Manning (on page 135 of his Finger Book) implies that pre-natal exposure to estrogen correlates with later schizotypy (or mild PSD). As I argue in The Imprinted Brain, there is very considerable evidence of feminizing trends in the brains and cognition of psychotics, and as I also pointed out in a recent post, researchers associated with a rival theory reported that there is a measurable link between being female and having a tendency to PSD. If this is indeed the case, it suggests a prediction unique to the imprinted brain theory that further research in relation to RORA might be able to test. This is the possibility that up-regulation of RORA expression might be implicated in PSD just as its down-regulation evidently is in ASD.

In that event, RORA would emerge, not only as a candidate gene for ASD, but one implicated in PSD as well. No other theory even hints at this, and were it to be found to be the case, the imprinted brain theory would be even more spectacularly vindicated by RORA than it has been already.

(With thanks and acknowledgement to Jonas Förare for bringing these findings to my attention.)