The genetic predisposition to longevity acts through behavioral phenotypes in females

The discovery of genetic factors for the predisposition of longevity is promising but their functional role and clinical relevance remain largely unclear. Based on results from a large genome-wide association study (GWAS) on human longevity (N ≈ 390,000) we identified six phenotype categories belonging to behavioral and psychiatric traits showing significant genetic correlations using LD Hub. We validated these genetic correlations on the phenotype level in a general population sample using a polygenic risk score (PRS) based on the longevity GWAS as proxy for longevity (N ≈ 8190; Study of Health in Pomerania). The behavioral phenotypes education, smoking and body mass index (BMI) were highly associated with the PRS for longevity especially in females (p_education=0.003, p_smoking=0.049, p_BMI=2.0E-4) with increased rates for higher education, lower smoking rates and decrease in BMI attributed to a higher PRS for longevity. Moreover, the psychiatric phenotypes depression and subjective health complaints showed significant associations (p_DEPR=0.032, p_SHC=0.002) in females only. Generally, a higher genetic predisposition for longevity had a stronger association with behavioral phenotypes in females than in males. It is unclear what causes the higher ``behavioral heterogeneity'' in males but different biological mechanisms might be involved. Sensitivity analyses showed that the association for the PRS for longevity with BMI and smoking were robust against adjustment with the PRS for BMI and smoking. In conclusion, our analyses demonstrated that genetic information obtained from highly powered GWAS for longevity revealed a clear behavioral signature on the phenotype level in a smaller population based sample.