Genome-wide association studies (GWAS) in complex diseases: advantages and limitations.

Classic inherited diseases are caused by a single gene mutation, often with serious consequences for the organism, but are fortunately rare. Acquired diseases, on the contrary, are due to environmental factors. However, many of the most prevalent diseases are actually the result of the combination of hereditary and environmental factors. Many common disorders such as osteoporosis, arthritis, diabetes or hypertension tend to cluster in families, reflecting their hereditary component (although there may also be shared environmental factors). The importance of hereditary factors in osteoporosis is large and, for example, accounts for between 50% and 80% of the variability of bone mass.1 Genetic epidemiology studies showed that, unlike classical hereditary diseases, the risk for these disorders is not explained by the alteration of a single gene. Hence the name of “polygenic” or “complex” diseases. By sequencing the human genome it was ascertained that there are many inter-individual variations in DNA. Contrary to mutations, these variations are quite common and in many cases their functional impact is limited (in fact, most occur in non-coding regions) and were called “polymorphisms”. Among them, the single nucleotide polymorphisms (SNPs) consist of simply the change of one base for another. They are very frequent, about 15 million in the genome. There are also frequent repeat polymorphisms, which consist of groups of a few nucleotides that are repeated variable number of times in individuals. More recently, another form of DNA variation was identified and called “variation in the number of copies.” It consists of relatively large regions of the genome, thousands of nucleotides, which in some individuals are repeated on the same or on different chromosomes. The fact that complex diseases do not follow a classic pattern of inheritance, i.e. they cannot be explained by a single gene disorder, along with the discovery of the frequency of polymorphisms led to the hypothesis of “common illnesses common variants”. This assumes that common complex diseases are the result of the combined effect of many common polymorphisms in the population.