Mapping complex and monogenetic disorders: methods and applications

PhD ceremony: mw. A.M. Szperl, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Mapping complex and monogenetic disorders: methods and applications

Promotor(s): prof. T.N. Wijmenga

Faculty: Medical Sciences

Each of us is a unique individual and we all differ in looks, personality, and talents; some of us get sick more often or can run faster than others. These characteristics, or traits, are determined by exogenous factors (such as air pollution, infections) and inherited factors (all the information carried in our DNA). Monogenetic traits (majority of rare disorders) are controlled by one gene and the influence of exogenous factors is very limited, whereas complex traits (e.g., body mass index) are defined by multiple genes inherited from parents (e.g., the genes controlling metabolism) and by the environment you live in (e.g., diet, exercise). To prevent and cure diseases, medical genetic studies focus on investigating aberrations in our DNA to explain complex (e.g., cancer, type 1 diabetes, celiac disease) and monogenic disorders (e.g., hemophilia, Huntington’s disease).

This thesis presents an overview of different tools and approaches used in human genetics. Both recessively and dominantly inherited monogenic as well as complex diseases in family and population based set-ups were studied. By using positional-candidate mapping, cross ethnic fine-mapping and genome wide sequencing the causal mutations for several of these diseases were identified, or the chromosomal region containing the causal gene was narrowed down. Finally, the next generation sequencing method which can be used to explain most of the monogenic and some of the complex disorders at present and in the near future is extensively discussed.