BACKGROUND: C-reactive protein (CRP) is a moderately heritable marker of systemic inflammation that is associated with adverse physical and mental health outcomes. Identifying factors associated with genetic liability to elevated CRP in childhood may inform our understanding of variability in CRP that could be targeted to prevent and/or delay the onset of related health outcomes. METHODS: We conducted a phenome-wide association study (PheWAS) of genetic risk for elevated CRP (i.e. CRP polygenic risk score [PRS]) among children genetically similar to European ancestry reference populations (median analytic n = 5,509) from the Adolescent Brain and Cognitive DevelopmentSM (ABCD) Study. Associations between CRP PRS and 2,377 psychosocial and neuroimaging phenotypes were estimated using independent mixed effects models. Post hoc analyses examined whether: (1) covarying for measured body mass index (BMI) or removing the shared genetic architecture between CRP and BMI altered phenotypic associations, (2) sex moderated CRP PRS associations, and (3) associations are unconfounded by assortative mating or passive gene-environment correlations (using a within-family analyses). Multiple testing was adjusted for using Bonferroni and false discovery rate (FDR) correction. RESULTS: Nine phenotypes were positively associated with CRP PRS after multiple testing correction: five weight- and eating-related phenotypes (e.g. BMI, overeating), three phenotypes related to caregiver somatic problems (e.g. caregiver somatic complaints), as well as weekday video watching (all ps = 1.2 x 10-7 - 2.5 x 10-4, all pFDRs = 0.0002 - 0.05). No neuroimaging phenotypes were associated with CRP PRS (all ps = 0.0003 - 0.998; all pFDRs = 0.08 - 0.998) after correction for multiple testing. Eating and weight-related phenotypes remained associated with CRP PRS in within-family analyses. Covarying for BMI resulted in largely consistent results, and sex did not moderate any CRP PRS associations. Removing the shared genetic variance between CRP and BMI attenuated all relationships; associations with weekday video watching, caregiver somatic problems and caregiver report that the child is overweight remained significant while associations with waist circumference, weight, and caregiver report that child overeats did not. DISCUSSION: Genetic liability to elevated CRP is associated with higher weight, eating, and weekday video watching during childhood as well as caregiver somatic problems. These associations were consistent with direct genetic effects (i.e., not solely due to confounding factors like passive gene-environment correlations) and were independent of measured BMI. The majority of associations with weight and eating phenotypes were attributable to shared genetic architecture between BMI and inflammation. The relationship between genetics and heightened inflammation in later life may be partially attributable to modifiable behaviors (e.g. weight and activity levels) that are expressed as early as childhood.

The authors have declared no competing interest.

Data for this study were provided by the Adolescent Brain Cognitive Development (ABCD) study℠, which was funded by awards U01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, and U24DA041147 from the NIH and additional federal partners (https://abcdstudy.org/federal-partners.html). This study was supported by R01 DA054750. Authors received funding support from NIH: AJG was supported by NSF DGE-213989. SEP was supported by F31AA029934. NRK was supported by K23MH12179201. ECJ was supported by K01DA051759. ASH was supported by K01AA030083. ZAL was supported by the McDonnell Center for Systems Neuroscience at Washington University. DAAB was supported by K99 AA030808. RB received additional support from R01-AG045231, R01-AG061162, R21-AA027827, R01-DA046224, and U01-DA055367. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee/IRB of Washington University in St. Louis gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors.