4 Discussion
4.1 Main Findings
In a cohort of well-characterized nulliparous pregnant people, a
GRSBW, derived from a set of previously was modestly
associated with infant BW. However, its association with BW was not
statistically significant among participants who self-identified as
Black, Asian, or had an unknown race, or among those with AFR, EAS, SAS,
or UNK genetically predicted ancestry. Our findings suggest that the
GRSBW does not fully generalize to racially or
genetically diverse groups.
4.2 Interpretation
Our findings are concordant with other studies assessing the
relationship between race and fetal growth. Across a variety of
contexts, studies have found that race is associated with differences in
fetal growth among both unselected and low risk groups.(16-18) In our
study, both self-identified race and genetically predicted ancestry were
associated with gestational age-adjusted BW, even after controlling for
sex and GRSBW. Our finding that the
GRSBW was not consistently associated with BW across
non-European ancestry groups is also consistent with existing studies of
other conditions. Polygenic risk scores derived in primarily European
cohorts perform significantly less well in participants of non-European
descent for multiple conditions, including venous thromboembolism,
coronary artery disease, heart disease, hypertension, chronic kidney
disease, and cancer.(19-25) The non-generalizability of genetic findings
to diverse populations is a critical gap with the potential to
exacerbate existing disparities.(26, 27) Our findings add to this
important body of work by extending it to fetal growth, which holds
considerable clinical relevance in perinatal medicine.
Our findings have several implications for future efforts in this area.
First, our results demonstrating that GRSBW is not
associated with BW in many ancestry groups, and that genetically
predicted ancestry remains independently associated with BW after
controlling for GRSBW, suggests that additional work is
needed to achieve equity in the performance of genetic risk scores for
BW prediction. Methods to support multi-ancestry polygenic risk score
derivation are now available and are promising in their ability to
equitably leverage genotypes for trait prediction. However, but such
methods still depend on the availability of discovery cohorts that
themselves are diverse, if not globally representative.(28-32) As
precision medicine advances its ability to improve recognition of
diseases such as fetal growth restriction and thereby allow for earlier
surveillance or treatment, genetic risk scores that perform better in
some populations than others have the potential to exacerbate inequities
in adverse pregnancy outcomes. Second, two results suggest that there
are additional unaccounted-for factors linking race to fetal growth: the
lack of association between GRSBW and BW in multiple
self-identified racial groups, and that self-identified race remains
associated with BW after controlling for GRSBW. As
noted, the GRSBW is likely insufficiently capturing the
genetic components of this association. However, as race is a social
construct, the persistent association between race and BW can also be
linked to systematic differences in environmental and social exposures
that are known to contribute to racial health disparities. It is also
plausible that there are epigenetic influences reflecting the
transgenerational impact of racism and other forms of deprivation,
oppression, and hardship imposed on minoritized populations. These
factors and their complex relationships to the genetics of fetal growth
remain to be clarified and warrant further investigation.
4.3 Strengths and Limitations
Strengths of our study included the use of a large, multicenter U.S.
obstetric cohort with geographical and racial diversity. The nuMoM2b
protocol provides both standardized specimen collection and validated
outcomes ascertainment, and we used externally derived BW-associated
SNPs for GRSBW assessment, adding to the rigor and
validity of our analysis. Additionally, our assessment of
GRSBW using two distinct approaches (both
self-identified race and genetically predicted continental ancestry
groups) demonstrates that the lack of generalizability is a robust
finding.
Our study also had limitations. The need to map SNPs derived from
reference build GRCh37 to GRCh38, ultimately leading to the use of 73
rather than 86 SNPs may have reduced the strength of the overall
association between the GRSBW and BW. Also, it is
possible that the lack of association between the GRSBWand BW is due to the sample sizes of each group, especially for the
smallest groups, such as Native Hawaiian/Pacific Islander or American
Indian/Alaska Native. However, sample size limitations are unlikely to
fully explain the lack of association, as the GRSBW was
associated with BW in the multiracial group (n=508) and was very nearly
significant among those of SAS predicted ancestry (n=274), both of which
had smaller sample sizes than the largest groups in which
GRSBW was not associated with BW.