Heredity in Parkinson's disease. From rare mutations to common genetic risk factors.

Research output: ThesisDoctoral Thesis (compilation)


This study investigated genetic causes of Parkinson's disease (PD) and parkinsonism in southern Sweden.
The extensive Lister Family with parkinsonism caused by duplications and triplications of the gene for alpha-synuclein (SNCA) was studied. Clinical, genetic and genealogical data were compiled and evaluated. Thirty-five family members with parkinsonism were identified. They share a characteristic clinical subtype of parkinsonism with marked dysfunction of the autonomic nervous system, behavioral changes and cognitive decline. The clinical phenotype, heredity and genetic background of 132 probands from Southern Sweden with PD or parkinsonism was examined. The SNCA, LRRK2, EIF4G1, VPS35, PINK1, ATXN2 and ATXN3 genes were analyzed in all probands; the PARKIN, PINK1 and DJ1 genes were tested in a subgroup of 23 patients with young onset or marked heredity. DNA from the brain tissue of 7 patients with parkinsonism was also analyzed. Common genetic risk factors in DNA samples collected within this study were analyzed in collaboration with other research groups.
Gene screening identified two rare causative mutations, SNCA A53T and LRRK2 N1437H. An additional patient was compound heterozygous for PARKIN R275W and R275Q mutations. Detailed information on their clinical picture is presented. We present the first neuropathological description of a patient with PD and LRRK2 N1437H mutation, showing
pronounced ubiquitin and moderate alpha-synuclein pathology. A heterozygous PINK1 G411S mutation was present in two PD patients but showed no clear co-segregation with the disease in their families. Screening of 1,107 patients and controls as well as meta-analysis of published reports from 7,800 individuals revealed that the PINK1 G411S mutation is a rare risk variant with a relatively large effect size (odds ratios 4.06-8.42). One multicenter study
confirmed that common variants in the SNCA and MAPT genes modify PD risk, and was large enough to refute gene-gene interaction between the MAPT and SNCA variants.
These results suggest that specific mutations in PD-genes cause characteristic disease subtypes. Despite extensive screening and a high proportion of familial cases, known pathogenic mutations could only explain a small proportion of parkinsonism in this cohort. This may indicate that mutations causing parkinsonism in the Scandinavian population remain to be discovered. Alternatively, familial clustering and sporadic occurrence of PD may be explained
by combinations of rare variants with relatively large effect size, such as PINK1 G411S.


Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Psychiatry
  • Geriatrics


  • Parkinson's disease, parkinsonism, genetics, alpha-synuclein, SNCA duplicaion, SNCA triplication, LRRK2, PARKIN, PARK2, VPS35, EIF4G1, rare variants, digenic inheritance, heritability
Original languageEnglish
Awarding Institution
Supervisors/Assistant supervisor
Award date2011 Oct 14
  • Lund University
Print ISBNs978-91-86871-44-4
Publication statusPublished - 2011
Publication categoryResearch

Bibliographic note

Defence details Date: 2011-10-14 Time: 14:00 Place: Segerfalksalen, Wallenberg Neurocentrum, Lund, Sweden External reviewer(s) Name: Nicholl, David J. Title: MD, MBChB, FRCP, PhD Affiliation: University of Birmingham, U.K. --- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Department of Psychogeriatrics (013304000), Division IV (013230800)

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