Human-genome gut-microbiome interaction in Parkinson's disease

The causes of complex diseases remain an enigma despite decades of epidemiologic research on environmental risks and genome-wide studies that have uncovered tens or hundreds of susceptibility loci for each disease. We hypothesize that the microbiome is the missing link. Genetic studies have shown that overexpression of alpha-synuclein, a key pathological protein in Parkinson9s disease (PD), can cause familial PD and variants at alpha-synuclein locus confer risk of idiopathic PD. Recently, dysbiosis of gut microbiome in PD was identified: altered abundances of three microbial clusters were found, one of which was composed of opportunistic pathogens. Using two large datasets, we show that the overabundance of opportunistic pathogens in PD gut is influenced by the host genotype at the alpha- synuclein locus, and that the variants responsible modulate alpha-synuclein expression. This is the first demonstration of interaction between genetic factors in the human genome and the dysbiosis of gut microbiome in PD.