• The Effect of Variants in Five Genes in the Glucagon Pathway on Type 2 Diabetes Risk and Diabetes-Related Traits

      Winters, Alexandra Holbrooke; Pollin, Toni; 0000-0003-1215-726X (2016)
      The CDC estimates that 29.1 million Americans have type 2 diabetes, which is currently the seventh leading cause of death in the US. It has been proposed that disordered glucagon regulation is a major contributor to the diabetic phenotype. We hypothesized that variants in five genes in the glucagon pathway are associated with response of diabetes-related glucose, insulin, and body composition traits to three antidiabetic interventions in the DPP and that rare coding variants would be enriched compared to other populations and associated with type 2 diabetes and diabetes-related traits in the Old Order Amish (OOA). We have discovered an association between the GCG variant, rs5649, that is predicted to modify the consensus splice site, with increased baseline-adjusted fasting glucose at one year in the metformin and placebo groups but not in the other two treatment groups, suggesting that it may change the structure of glucagon and decrease the ability of metformin to reduce glucagon signaling. We have performed the only known study of a PCSK2 coding variant common in any population. We found this variant, R430W, and the GCGR variant D458H to be twice as common among OOA individuals with diabetes as those with normal or impaired glucose tolerance, although this difference is not statistically significant. In addition, we examined the relationship between the GCGR coding variant G40S and type 2 diabetes risk that has been previously reported and did not see an association despite being better powered than previous studies because of the increased allele frequency of 14% in the OOA population. Finally, we described the only reported GCGR G40S homozygotes, none of whom have type 2 diabetes. In sum, we have provided data on the effects of variants in five genes in the glucagon pathway that can be used in future work to understand the contribution of the glucagon pathway to type 2 diabetes and to inform the development of antidiabetic treatments targeting this pathway.
    • Genetics of mood disorder diagnosis, behavioral endophenotypes, and cognition in the Old Order Amish founder population

      Humphries, Elizabeth; Ament, Seth A. (2021)
      Mood disorders, including major depression and bipolar disorder, represent a substantial public health burden. Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous loci that together account for part of the risk, but pathophysiological mechanisms have been elusive. Individual common variants confer very small risk, and samples have been underpowered to detect rare variants with larger effects. Extended pedigrees from population isolates could address these challenges, as some risk-conferring alleles may be highly enriched, relative to the broader population. Here I report a GWAS of mood disorders in an Old Order Amish (OOA) founder population. By integrating genetic and phenotypic data from three independently collected OOA cohorts enriched for mood disorders with OOA population controls (total n=1,672), I identified four genome-wide significant risk loci, 2 of which are novel. The observed effect sizes of the associated loci are substantially greater than those identified in the broader population, and the risk-associated haplotypes harbor otherwise rare coding variants enriched in OOA. At one locus, I identified a population-enriched, non-synonymous variant in the CUX1 alternative splicing product associated with >3-fold relative risk. Quantitative behavioral and neurocognitive traits in a sub-set of 314 subjects revealed effects of risk variants on sub-clinical depressive symptoms and working memory. These findings provide insight into the genetic architecture of mood disorders and provide a substrate for mechanistic and clinical studies.