The last decade has seen great advances in complex disease genetics. In particular, genome-wide association studies have identified a large number of gene regions implicated in common disorders. However, much is still unknown about the genetic architecture of disease. In general, findings from genetic studies have explained less variation than expected from epidemiological data. Where is the "missing heritability"?
Parkinson's disease re-sequencing
In the case of Parkinson's disease, there are both rare mutations causing familial forms of parkinsonism, and common variants with a small effect on the risk for sporadic disease. In reality, this distinction is probably less absolute, with genetic variants across a spectrum of different frequencies and effect sizes. Understanding the distribution and interplay of all these disease relevant variants is currently one of the most central challenges in complex genetics.
In a current project, we explore the genetic variation in a large panel of Parkinson genes in Norwegian samples. We use modern technologies for DNA capture and sequencing in pools to effectively investigate many relevant genes in hundreds of patients, all in one experiment (for methods see Pihlstrøm et al, 2014). The analyses include both genes causing monogenic disease, genes identified through genome-wide association studies in sporadic patients, and genes implicated in related neurodegenerative diseases.
Re-sequencing of hereditary ataxia and spastic paraplegia genes
Cerebellar ataxias and spastic paraplegias are rare inherited neurodegenerative disorders. The main clinical symptoms are gait disturbances due to spasticity in the lower limbs and/or impaired coordination control (ataxia). The clinical presentation can range from pure cerebellar ataxia or pure spastic paraplegia to more complex forms that often combine both ataxia and spasticity together with other neurological symptoms.
All types of genetic inheritance are represented and the genetic heterogeneity is remarkable with at least 80 genetic loci linked with the disorders. Routine tests have been established for the most common forms. Since a family history may be missing for a variety of reasons, such as small families or de novo mutations, the diagnosis remains predominantly clinical. Thus, currently a large number of patients are left without a genetic diagnosis.
In a new project together with Prof. Chantal Tallaksen's group, we have re-sequenced all hereditary ataxia and spastic paraplegia genes in >100 Norwegian samples, all in one experiment. The purpose of the study is to examine how many patients that can receive a genetic diagnosis by the use of modern sequencing technology.
Main responsible for project: Dr. Zafar Iqbal