W21. SHARED GENETIC ARCHITECTURE OF EARLY-LIFE NEURODEVELOPMENTAL CONDITIONS AND LATE-LIFE NEURODEGENERATIVE DISEASES

The first generation of individuals diagnosed with neurodevelopmental conditions such as autism spectrum disorder and attention-deficit/hyperactivity disorder are now entering late adulthood. Emerging evidence suggests phenotypic correlations between early-life neurodevelopmental conditions and late-life neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. While clinical and biological links between these groups of disorders have been proposed, it remains unclear whether they share a common genetic architecture. Familial co-aggregation indicates possible genetic overlap, but genotype-based investigations have thus far been limited—focusing largely on genome-wide correlation estimates or candidate gene studies. We leveraged the latest summary statistics from large-scale genome-wide association studies of autism spectrum disorder, attention-deficit/hyperactivity disorder, Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis to investigate shared genetic architecture at multiple levels. We applied three complementary approaches: genome-wide correlation using linkage disequilibrium score regression, local genetic correlation using LAVA, and polygenic overlap estimation using MiXeR. We also conducted Mendelian randomization to explore potential causal pathways. Consistent with prior studies, we observed marginal genome-wide genetic correlations between neurodevelopmental and neurodegenerative conditions (all global Rg between –0.11 and 0.16; p > 0.5), and little evidence of causal links using Mendelian randomization. However, local genetic correlation analyses identified 17 loci with statistically significant correlations—both positive and negative—after correction for multiple testing. These included 9 loci for Alzheimer’s disease, 6 for Parkinson’s disease, and 2 for amyotrophic lateral sclerosis, each associated with either autism spectrum disorder or attention-deficit/hyperactivity disorder, suggesting region-specific pleiotropy. MiXeR revealed a key asymmetry: neurodevelopmental conditions, particularly autism spectrum disorder, were highly polygenic, with thousands of independent variants contributing to heritability, whereas neurodegenerative diseases showed substantially lower polygenicity. This imbalance likely obscures genome-wide genetic overlap. However, when viewed from the perspective of neurodegenerative conditions, a substantial proportion of their heritability—up to approximately 50% in the case of Alzheimer’s disease—was attributable to variants also associated with autism spectrum disorder or attention-deficit/hyperactivity disorder. Despite low global genetic correlations, substantial polygenic overlap exists between neurodevelopmental and neurodegenerative diseases, particularly when analyses are anchored on the genetic architecture of neurodegenerative conditions. These findings suggest that standard genome-wide correlation metrics may underestimate shared genetic risk due to opposing effect directions and marked differences in polygenicity. Methods that directly model causal variant overlap offer a clearer view of the convergent genetic basis that may underlie observed epidemiological associations and familial co-aggregation patterns.