| 000 | 03820 am a22003133u 4500 | ||
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| 042 | _adc | ||
| 100 | 1 | 0 |
_aBolhuis, Koen _eauthor _92940 |
| 700 | 1 | 0 |
_aMulder, Rosa H. _eauthor _92941 |
| 700 | 1 | 0 |
_ade Mol, Casper Louk _eauthor _92942 |
| 700 | 1 | 0 |
_aDefina, Serena _eauthor _92943 |
| 700 | 1 | 0 |
_aWarrier, Varun _eauthor _92944 |
| 700 | 1 | 0 |
_aWhite, Tonya _eauthor _92945 |
| 700 | 1 | 0 |
_aTiemeier, Henning _eauthor _92946 |
| 700 | 1 | 0 |
_aMuetzel, Ryan L. _eauthor _92947 |
| 700 | 1 | 0 |
_aCecil, Charlotte A. M. _eauthor _92948 |
| 245 | 0 | 0 | _aMapping gene by early life stress interactions on child subcortical brain structures: A genome-wide prospective study |
| 260 | _c2022-11-16. | ||
| 500 | _a/pmc/articles/PMC7614163/ | ||
| 500 | _a/pubmed/36777645 | ||
| 520 | _aBACKGROUND: Although it is well-established that both genetics and the environment influence brain development, they are typically examined separately. Here, we aimed to prospectively investigate the interactive effects of genetic variants-from a genome-wide approach-and early life stress (ELS) on child subcortical brain structures, and their association with subsequent mental health problems. METHOD: Primary analyses were conducted using data from the Generation R Study (N = 2257), including genotype and cumulative prenatal and postnatal ELS scores (encompassing life events, contextual risk, parental risk, interpersonal risk, direct victimisation). Neuroimaging data were collected at age 10 years, including intracranial and subcortical brain volumes (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus). Genome-wide association and genome-wide-by-environment interaction analyses (GWEIS, run separately for prenatal/postnatal ELS) were conducted for eight brain outcomes (i.e., 24 genome-wide analyses) in the Generation R Study (discovery). Polygenic scores (PGS) using the resulting weights were calculated in an independent (target) cohort (adolescent brain cognitive development Study; N = 10,751), to validate associations with corresponding subcortical volumes and examine links to later mother-reported internalising and externalising problems. RESULTS: One GWEIS-prenatal stress locus was associated with caudate volume (rs139505895, mapping onto PRSS12 and NDST3) and two GWEIS-postnatal stress loci with the accumbens (rs2397823 and rs3130008, mapping onto CUTA, SYNGAP1, and TABP). Functional annotation revealed that these genes play a role in neuronal plasticity and synaptic function, and have been implicated in neuro-developmental phenotypes, for example, intellectual disability, autism, and schizophrenia. None of these associations survived a more stringent correction for multiple testing across all analysis sets. In the validation sample, all PGS(genotype) were associated with their respective brain volumes, but no PGS(GxE) associated with any subcortical volume. None of the PGS associated with internalising or externalising problems. CONCLUSIONS: This study lends novel suggestive insights into gene-environment interplay on the developing brain as well as pointing to promising candidate loci for future replication and mechanistic studies. | ||
| 540 | _a | ||
| 540 | _ahttps://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited https://creativecommons.org/licenses/by/4.0/. | ||
| 540 | _ahttps://creativecommons.org/licenses/by/4.0/This work is licensed under a CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) International license. | ||
| 546 | _aen | ||
| 690 | _aArticle | ||
| 655 | 7 |
_aText _2local |
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| 786 | 0 | _nJCPP Adv | |
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_uhttp://dx.doi.org/10.1002/jcv2.12113 _zConnect to this object online. |
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