CAN SOME DISEASES BE BOTH MONOGENIC AND COMPLEX?
It should be noted that for many, and probably most diseases, there is a spectrum of genetic causes from monogenic/Mendelian to complex. That is, some highly penetrant variants can be strongly associated with a disease, along with other variants of low effect. Examples include cancer, Alzheimer’s disease, and heart diseases in which both monogenic and complex forms occur in different families. These forms can have different disease effects. Take as an example Alzheimer’s disease. There are early onset cases in which particular variants in the APP or presenilin-1 or 2 genes almost always cause familial forms of the disease. That is, if a family member has the disease and the child gets the same variants, there is a good chance the child will develop Alzheimer’s disease at a relatively young age.
For late onset Alzheimer’s, the situation is more complex. One major gene associated with late onset Alzheimer’s is the apolipoprotein E gene (APOE). Twenty-five to thirty percent of the population has a variant called ApoE4 that is commonly associated with the disease. (Males without this mutation have a 17% chance of acquiring the disease; those with one copy have a 25% chance; and those with both copies mutated have a 60% chance.) Although the ApoE4 allele is present in about 40% of people who have Alzheimer’s, it is not the only factor responsible for the disease, because many people who have two copies of this allele do not develop the disease, and similarly, many others who get the disease do not have the ApoE4 allele. Thus, other genetic and environmental factors contribute to late onset Alzheimer’s, and many other genetic loci of lower effect have been identified. Interestingly, in regards to ApoE, there are also alleles that are protective (ApoE2) and reduce the chances of getting Alzheimer’s. Thus, mutations in various genes can cause familial disease, and major and minor genetic risk factors exist.
Two other examples of complex diseases or syndromes with a major genetic component—as well as other minor alleles—are age-related macular degeneration and autism. Age-related macular degeneration results in blindness, and one major locus (HTRAX) accounts for approximately one-half of genetic cases. For autism, there are mutations that cause strong autism-like effects in children (e.g., Rett syndrome and Angelman syndrome in children, which have mutations in the MECP2 and UBE3A genes, respectively). There are also many other mutations that likely do not cause the disorder by themselves but likely do so in conjunction with other genetic mutations or environmental factors. Thus, overall, for most diseases there is likely to be a spectrum of risk genes, stretching from those that give very strong effects to those that result in much weaker ones.