This analysis revealed substantial heterogeneity in the human genome with regard to disease susceptibility. The majority of bins (13,900 of 15,157; 92%) did not contain any disease-associated SNPs. In contrast, only ten bins (2 Mb or 0.06% of the genome) showed statistically significant enrichment (p<0.05) for disease association, with two strong ‘peaks’ (p<0.0001) of multi-disease association. The largest peak spanned four neighboring bins (800 kb) that contain the gene-rich MHC locus on chromosome 6p21 (). SNPs in this bin were linked to 24 unique diseases, most of which were autoimmune in nature (e.g. asthma, inflammatory bowel disease, lupus, Hodgkins Disease, ), and not classical disease of aging. This finding confirms the well-established pathogenic role of MHC polymorphisms in the development of diverse autoimmune diseases (Fernando et al. 2008; Rioux et al. 2009). Therefore, while the association of the MHC locus with autoimmune diseases is not surprising, this finding serves as a positive control for the analysis.
It is also worth noting what was not associated with broad disease susceptibility: conserved pathways that modulate longevity in model organisms (e.g. Insulin/IGF-1 signaling, mTOR signaling, reactive oxygen species signaling, Sirtuins, etc). It is possible that regulation of these pathways is not variable among human populations or that these pathways do not modulate general disease resistance in humans, but we think more likely this observation reflects a lack of power of the GWAS meta-analysis approach. Accordingly, SNPs near IGF1R, FOXO3A, and AKT1 have been associated with longevity in candidate studies and pedigree analyses (Suh et al. 2008; Pawlikowska et al. 2009; Sebastiani et al. 2012), suggesting an association of these loci with age-associated conditions may emerge in genome-wide analyses with further study. Nonetheless, this unbiased meta-analysis of results from ~2.3 million patients only identifies polymorphic regulation of cellular senescence and immunity as general determinants of genetic susceptibility to a host of human diseases, with in particular a striking association of senescence with age-associated disease. These genetic data support the therapeutic targeting of these specific pathways to promote broad disease resistance and augment the human health span.
Genome-Wide Association studies (GWAS) offer an unbiased means to understand the genetic basis of traits by identifying single nucleotide polymorphisms (SNPs) linked to causal variants of complex phenotypes. GWAS have identified a host of susceptibility SNPs associated with many important human diseases, including diseases associated with aging. In an effort to understand the genetics of broad resistance to age-associated diseases (i.e. ‘wellness’), we performed a meta-analysis of human GWAS. Toward that end, we compiled 372 GWAS that identified 1,775 susceptibility SNPs to 105 unique diseases and used these SNPs to create a genomic landscape of disease susceptibility. This map was constructed by partitioning the genome into 200 kb ‘bins’ and mapping the 1,775 susceptibility SNPs to bins based on their genomic location. Investigation of these data revealed significant heterogeneity of disease association within the genome, with 92% of bins devoid of disease-associated SNPs. In contrast, 10 bins (0.06%) were significantly (p<0.05) enriched for susceptibility to multiple diseases, 5 of which formed two highly significant peaks of disease association (p<0.0001). These peaks mapped to the Major Histocompatibility (MHC) locus on 6p21 and the INK4/ARF (CDKN2a/b) tumor suppressor locus on 9p21.3. Provocatively, all 10 significantly enriched bins contained genes linked to either inflammation or cellular senescence pathways, and SNPs near regulators of senescence were particularly associated with disease of aging (e.g. cancer, atherosclerosis, type 2 diabetes, glaucoma). This analysis suggests that germline genetic heterogeneity in the regulation of immunity and cellular senescence influences the human health span. https://www.nature.com/articles/nature13193