Dynamic interaction between fetal adversity and a genetic score reflecting dopamine function on developmental outcomes at 36 months

Adrianne R Bischoff, Irina Pokhvisneva, Étienne Léger, Hélène Gaudreau, Meir Steiner, James L Kennedy, Kieran J O'Donnell, Josie Diorio, Michael J Meaney, Patrícia P Silveira, MAVAN research team, Adrianne R Bischoff, Irina Pokhvisneva, Étienne Léger, Hélène Gaudreau, Meir Steiner, James L Kennedy, Kieran J O'Donnell, Josie Diorio, Michael J Meaney, Patrícia P Silveira, MAVAN research team

Abstract

Background: Fetal adversity, evidenced by poor fetal growth for instance, is associated with increased risk for several diseases later in life. Classical cut-offs to characterize small (SGA) and large for gestational age (LGA) newborns are used to define long term vulnerability. We aimed at exploring the possible dynamism of different birth weight cut-offs in defining vulnerability in developmental outcomes (through the Bayley Scales of Infant and Toddler Development), using the example of a gene vs. fetal adversity interaction considering gene choices based on functional relevance to the studied outcome.

Methods: 36-month-old children from an established prospective birth cohort (Maternal Adversity, Vulnerability, and Neurodevelopment) were classified according to birth weight ratio (BWR) (SGA ≤0.85, LGA >1.15, exploring a wide range of other cut-offs) and genotyped for polymorphisms associated with dopamine signaling (TaqIA-A1 allele, DRD2-141C Ins/Ins, DRD4 7-repeat, DAT1-10- repeat, Met/Met-COMT), composing a score based on the described function, in which hypofunctional variants received lower scores.

Results: There were 251 children (123 girls and 128 boys). Using the classic cut-offs (0.85 and 1.15), there were no statistically significant interactions between the neonatal groups and the dopamine genetic score. However, when changing the cut-offs, it is possible to see ranges of BWR that could be associated with vulnerability to poorer development according to the variation in the dopamine function.

Conclusion: The classic birth weight cut-offs to define SGA and LGA newborns should be seen with caution, as depending on the outcome in question, the protocols for long-term follow up could be either too inclusive-therefore most costly, or unable to screen true vulnerabilities-and therefore ineffective to establish early interventions and primary prevention.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Categorization of the BWR into…
Fig 1. Categorization of the BWR into three groups and levels of significance for the interaction between BWR and the dopamine genetic score.
Groups (SGA, AGA and LGA) are categorized according to different cut-offs (A and B). Group II was used as the reference group (AGA) for all comparisons. The graph depicts the result for a fixed cut-off A and changing cut-off B. Each dot in the plot corresponds to the difference in the estimated β for DA multilocus between SGA and AGA (circles) or LGA and AGA (triangles).
Fig 2. Estimated β for dopamine multilocus…
Fig 2. Estimated β for dopamine multilocus score.
A range of SGA cut-offs is shown on the x axis, and LGA cut-offs are depicted on the y axis. Black signs show interactions that are not significant (p> = 0.05), red signs represent interactions that are statistically significant (p

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