72. THE SHARED GENETIC POTENTIATORS OF BIPOLAR DISORDER AND MODERN HUMAN MIGRATORY BEHAVIOR

Lucas Casten; Jacob Michaelson

doi:10.1016/j.euroneuro.2024.08.186

The backbone of human progress is migration, allowing for ideas to cross physical and cultural barriers. Previous research has explored the profound impacts of ancient migrations on human genetic diversity, but the inverse – the impact of genetic variation on modern migratory behavior – is less clear. We sought to better understand the genetic potentiators of migratory behavior and its relation to mental health traits. We investigated the effects of common genetic variation on migratory behavior by conducting a GWAS on the distance moved from birthplace of unrelated white British adults from the UK Biobank (N=282,178). Subsequent analyses using polygenic scores of migratory behavior in independent samples revealed associated behavioral profiles in adults (SPARK, N=3,846) and generalization to migration distances of ancient humans in remains as old as 9,000 years (Allen Ancient DNA Resource, Pearson's R=0.1, p < 0.001, N=1,339). Both twin and molecular-based methods yielded significant heritability estimates, suggesting that migratory behavior has a biological basis (twin heritability=34.4%, SNP heritability=2.5%). We found 11 independently associated loci that map to genes linked to neurodevelopment and psychiatric risk, with the strongest signal coming from the transcription factor MEF2C (rs40504, p=8e-15). Analysis of our GWAS results showed numerous genetic correlations, including significant associations with: educational attainment (EA; rG=0.77), brain volume (rG=0.16), risk-taking (rG=0.15), and bipolar disorder (rG=0.14). GWAS by subtraction disentangled EA- and non-EA-related migration factors, and each of these showed evidence of shared genetic signal with bipolar disorder. The EA-related factor was broadly associated with health and cognition-promoting genetic factors, as well as traits indicating fragile social and family relationships (e.g., low satisfaction with friendships and family relations). The personal advantage combined with relationship difficulties are hypothesized to increase probability of a significant migration. The non-EA factor was genetically correlated with risk taking behavior (p <0.001). Convergent polygenic associations of bipolar risk and these two migration factors supported these interpretations: EA factor PGS and bipolar PGS were significantly associated with “I have trouble making or keeping friends” (p <0.05), while the non-EA factor PGS and bipolar PGS were associated with “My behavior is changeable” and “I feel restless or fidgety” and “My moods or feelings change suddenly” (all p <0.05). Finally, over 30 genes at FDR < 0.05 by MAGMA analysis overlap with those found in the bipolar GWAS, including PCDH17, BCL11A, NRXN1, and ATXN1. Migration behavior could be parsed into two genetically-potentiated factors: health and cognitive advantage coupled with propensity for weaker family and friend relationships, and restless, changeable behavior. Both factors showed a shared signal with bipolar disorder, and likely influence migratory behavior through different mechanisms. The EA factor would likely present more opportunities (via cognitive advantage) and simultaneously make it easier to pursue them due to reduced affinity for family and friends. The non-EA factor likely contributes to migratory behavior by conferring a more essential propensity to restlessness and impulsivity. Nothing to disclose.

72. THE SHARED GENETIC POTENTIATORS OF BIPOLAR DISORDER AND MODERN HUMAN MIGRATORY BEHAVIOR

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