Monogenic disorders are individually rare, run in families based on classic modes of inheritance termed Mendelian inheritance (autosomal dominant or recessive, X-linked), and are caused by variation within a single gene. The involved variants are rare and typically disrupt protein-coding genes thereby causing disease. Monogenic traits are however rare. Many–if not most–traits are associated with a familial risk, without demonstrating a typical Mendelian inheritance pattern. The lack of a Mendelian inheritance pattern however does not exclude a genetic origin. These common traits are classified as complex–or multifactorial–traits, caused by variation within multiple genes (polygenic) and environmental factors.

Here, we explain how complex trait genetics can be studied, some key concepts, and whether the current findings can be used in clinical decision-making. We will focus on inflammatory bowel disease (IBD), a prototypical complex disease, although the explanations may apply also to other complex diseases such as coeliac disease, primary sclerosing cholangitis, irritable bowel syndrome and sporadic colorectal cancer.