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Evaluating indirect genetic effects of siblings using singletons.

ABSTRACT: Estimating effects of parental and sibling genotypes (indirect genetic effects) can provide insight into how the family environment influences phenotypic variation. There is growing molecular genetic evidence for effects of parental phenotypes on their offspring (e.g. parental educational attainment), but the extent to which siblings affect each other is currently unclear. Here we used data from samples of unrelated individuals, without (singletons) and with biological full-siblings (non-singletons), to investigate and estimate sibling effects. Indirect genetic effects of siblings increase (or decrease) the covariance between genetic variation and a phenotype. It follows that differences in genetic association estimates between singletons and non-singletons could indicate indirect genetic effects of siblings if there is no heterogeneity in other sources of genetic association between singletons and non-singletons. We used UK Biobank data to estimate polygenic score (PGS) associations for height, BMI and educational attainment in self-reported singletons (N = 50,143) and non-singletons (N = 328,549). The educational attainment PGS association estimate was 12% larger (95% C.I. 3%, 21%) in the non-singleton sample than in the singleton sample, but the height and BMI PGS associations were consistent. Birth order data suggested that the difference in educational attainment PGS associations was driven by individuals with older siblings rather than firstborns. The relationship between number of siblings and educational attainment PGS associations was non-linear; PGS associations were 24% smaller in individuals with 6 or more siblings compared to the rest of the sample (95% C.I. 11%, 38%). We estimate that a 1 SD increase in sibling educational attainment PGS corresponds to a 0.025 year increase in the index individual's years in schooling (95% C.I. 0.013, 0.036). Our results suggest that older siblings may influence the educational attainment of younger siblings, adding to the growing evidence that effects of the environment on phenotypic variation partially reflect social effects of germline genetic variation in relatives.

SUBMITTER: Howe LJ

PROVIDER: S-EPMC9262210 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFamily members resemble each other in their propensity for aggression. In twin studies, approximately 50% of the variance in aggression can be explained by genetic influences. However, if there are genotype-environment correlation mechanisms, such as environmental manifestations of parental and sibling genotypes, genetic influences may partly reflect environmental influences. In this study, we investigated the importance of indirect polygenic score (PGS) effects on aggression.MethodsWe modeled the effect of PGSs based on 3 genome-wide association studies: early-life aggression, educational attainment, and attention-deficit/hyperactivity disorder (ADHD). The associations with aggression were tested in a within- and between-family design (37,796 measures from 7740 individuals, ages 3-86 years [mean = 14.20 years, SE = 12.03], from 3107 families, 55% female) and in a transmitted/nontransmitted PGS design (42,649 measures from 6653 individuals, ages 3-61 years [mean = 11.81 years, SE = 8.68], from 3024 families, 55% female). All participants are enrolled in the Netherlands Twin Register.ResultsWe found no evidence for contributions of indirect PGS effects on aggression in either a within- and between-family design or a transmitted/nontransmitted PGS design. Results indicate significant direct effects on aggression for the PGSs based on early-life aggression, educational attainment, and ADHD, although explained variance was low (within- and between-family: early-life aggression R2 = 0.3%, early-life ADHD R2 = 0.6%, educational attainment R2 = 0.7%; transmitted/nontransmitted PGSs: early-life aggression R2 = 0.2%, early-life ADHD R2 = 0.9%, educational attainment R2 = 0.5%).ConclusionsPGSs included in the current study had a direct (but no indirect) effect on aggression, consistent with results of previous twin and family studies. Further research involving other PGSs for aggression and related phenotypes is needed to determine whether this conclusion generalizes to overall genetic influences on aggression.

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Evaluating indirect genetic effects of siblings using singletons.

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