The Loop That Builds Itself. Polygenic Risk, Compensatory Family Norms, and Intergenerational Transmission of ADHD-Related Phenotypes

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is among the most heritable conditions in psychiatry (0.70-0.88). This paperproposes an integrative intergenerational model in which four mechanisms operate recursively: (1) polygenic risk elevatingliability across entire sibships, (2) compensatory parental strategies crystallizing into family norms, (3) gene-environmentcorrelation creating feedback loops, and (4) nonrandom mating concentrating polygenic burden across diagnosticboundaries. Preliminary epigenetic evidence suggests a possible additional biological mechanism for consolidating thesechanges. To examine the causal structure of cross-disorder associations, original two-sample Mendelian randomizationanalyses were conducted, complemented by PRS correlation analyses in 525 unrelated European-ancestry individuals. Resultsrevealed asymmetric causal pathways: ADHD liability exerted strong causal effects on ASD risk (OR = 1.575; p = 3.3 x 10-10)and SCZ risk (OR = 1.270; p = 2.6 x 10-5), while SCZ liability causally increased risk for both ASD (OR = 1.146; p = 6.8 x 10-8) andADHD (OR = 1.094; p = 3.1 x 10-3). The model reframes the nature-nurture dichotomy as biologically incoherent for highlyheritable, polygenically distributed psychiatric traits.