Studies of non-human species show that loci on non-homologous chromosomes can be in linkage disequilibrium (LD). I focus on the Framingham Heart Study (FHS) participants to explore whether the phenomenon of inter-chromosomal LD can be caused by non-stochastic bio-genetic mechanisms in the human genome and be associated with complex, polygenic phenotypes. This paper documents remarkably strong and extensive LD among SNPs at loci on multiple non-homologous chromosomes genotyped using two independent (Affymetrix 50 K and 500 K) arrays. The analyses provided compelling evidences that the observed inter-chromosomal LD was unlikely generated by stochasticity, population or family structure, or mis-genotyping. The analyses show that this LD is associated with complex heritable phenotypes characterizing poor health. The inter-chromosomal LD was observed in parental and offspring generations of the FHS participants. These findings suggest that inter-chromosomal LD can be caused by bio-genetic mechanisms possibly associated with favorable or unfavorable epistatic evolution. This phenomenon can challenge our understanding of the role of genes and gene networks in regulating complex, polygenic phenotypes in humans.