, 2013). In addition, mutations in a single causative gene may only be a portal to far greater molecular complexity. Thus, for example, FMR1, which is a neuronal polyribosome-associated RNA binding protein, has been shown to affect the translation of 842 mRNA transcripts ( Darnell et al., 2011) each with their own “downstream” biology; many of these individual targets are now being implicated for subtler contributions to complex, TSA HDAC order polygenic disease. The unexpected complexity of many monogenic brain disorders pales in comparison with the emerging complexity of common polygenic brain disorders, a challenge that is only now coming into view.

Because severe, highly penetrant mutations often produce marked decrements in reproductive fitness, they tend to be rare. In contrast, many common human illnesses result from the interaction of a large number of genes (polygenicity) in combination with nongenetic risk factors. Moreover, disease phenotypes tend to result from different combinations of genetic (and likely nongenetic) risk factors in different families and individuals. The use of the term VX-770 supplier “risk factor” rather than “cause” indicates that among polygenic disorders, any individual sequence variant (or

environmental factor) acts in a statistical rather than deterministic fashion. No single genetic variant is necessary or sufficient for the disorder phenotype and thus cannot be used to predict phenotype except in a probabilistic manner. Several important genetic results support polygenic models, for example, in schizophrenia and autism. The first is the finding that large numbers of common variants shape an individual’s disease risk. Statistical geneticists define a “polygene” from large constellations of common alleles that are observed (in one cohort) at slightly higher frequencies in schizophrenic patients than controls. When such alleles are subsequently evaluated in other cohorts, schizophrenic

patients are found to carry more such alleles (on average) than control subjects do. (Purcell et al., 2009). Within families, schizophrenic children of unaffected parents Rolziracetam also tend to have inherited more than the 50% of such alleles that they would be expected to have inherited by chance from parents heterozygous at the relevant loci (Ruderfer et al., 2011). These results suggest that one important component of genetic risk for a polygenic disorder such as schizophrenia arises from many small genetic nudges, rather than a single, hard shove. The polygenic model is also supported by rare alleles of larger effect. For example, a substantial minority of autistic patients (about 5%–10%), but only a small fraction of the general population (about 1%), have de novo deletions and duplications of large (>500 kb) genomic segments in their genomes.