# Behavioural, psychiatric, and cognitive phenotypes associated with numbers of repeats of the FRAXE allele on the FMR2 gene

## TL;DR

This study found that boys with higher numbers of FRAXE repeats (up to 60) show increased risks of certain behavioral and psychiatric issues, but no cognitive benefits.

## Contribution

The study is the first to investigate behavioral and psychiatric associations of FRAXE repeats within the normal range (<60) in a general population of boys.

## Key findings

- Boys with >24 FRAXE repeats had higher risks of psychosis-like experiences, eating disorders, and drug use.
- Increased FRAXE repeats were linked to better recognition of facial anger but no cognitive advantages.
- No evolutionary neurocognitive benefit was found for higher FRAXE repeat numbers in boys.

## Abstract

The FRAXE site on the X-chromosome has a variable number of trinucleotide repeats. The rare condition Fragile XE has >200 repeats, but most X chromosomes have <60 such repeats, with evidence of a bimodal distribution. It is known that when the number of repeats is <60, the repeat number can increase from mother to son, which raises the question as to whether there is an evolutionary advantage in the size of these repeats. This paper investigates whether the higher of the <60 repeats are associated with neurocognitive differences among boys in a general population. We hypothesised that although there was previous evidence of a link between higher numbers of repeats in the boys in this population with maternal grandmothers with schizophrenia, there may be cognitive or behavioural advantages to their grandsons of increased levels of repeats.

We compared 1951 behavioural, psychiatric, and cognitive outcomes of 5060 boys from the Avon Longitudinal Study of Parents and Children (ALSPAC) using a phenome scan.

We found that boys with relatively high levels of repeats (>24) had a higher risk of certain neurocognitive outcomes (P<0.01). Boys with >24 repeats were more likely to report: (a) psychosis-like experiences; (b) increased ability to recognise facial signs of anger; (c) increased risk of eating disorders; (d) increased likelihood of smoking cigarettes and using illicit drugs during adolescence than would be expected by chance. There was no sign of associations with cognitive abilities.

We concluded that there was little evidence that higher levels of the normal range of FRAXE repeats were associated with a difference in cognitive abilities, but there was evidence of increased reports of psychotic-like experiences and other behaviour problems in this group. There was no evidence of evolutionary neurocognitive advantage.

Overview: A specific area (FRAXE) on the X chromosome has a variable number of repeats of a GCC DNA sequence. Some adverse effects on boys’ cognitive ability are seen if there are 200+ repeats but less is known about cognitive/other effects associated with lower repeat numbers which rarely exceed 60. We examined neurocognitive and behavioural outcomes associated with <60 repeats of FRAXE and considered 1951 outcomes concerning behaviour, psychiatric disorders, temperament and cognitive abilities. For each outcome we determined whether it was a linear association (i.e. whether higher repeat numbers increased the risk of that outcome) and whether boys with 24–60 repeats had a greater risk than boys with <25 repeats. Analysis used 5060 boys participating in ALSPAC (Avon Longitudinal Study of Parents and Children), followed-up throughout childhood via structured self-completion questionnaires by mothers, fathers, teachers and the children themselves; testing within a clinical setting; linkage to national health and education records. Comparison of boys with >24 repeats with those with <25 repeats revealed more significant associations than expected by chance involving psychotic experiences, increased ability to identify facial anger expressions, eating disorders and addictive behaviours. Each association exhibited linear relationships (the higher the number of repeats the more likely the boy to have the outcome).

Why is it important? Evidence exists indicating numbers of FRAXE repeats on the mother’s X-chromosome can increase when that chromosome is inherited by her child. If this confers an evolutionary advantage, identifying the mechanism regarding which beneficial outcome may be responsible could be important.

Key takeaway: We concluded that higher numbers of repeats was unlikely to confer evolutionary advantages due to male neurocognitive outcomes, however, we suggest that other attributes of increased repeat numbers may be of evolutionary importance.