Identification of genetic modifiers of age-at-onset for familial Parkinson's disease

Hum Mol Genet. 2016 Sep 1;25(17):3849-3862. doi: 10.1093/hmg/ddw206. Epub 2016 Jul 11.


Parkinson's disease (PD) is the most common cause of neurodegenerative movement disorder and the second most common cause of dementia. Genes are thought to have a stronger effect on age-at-onset of PD than on risk, yet there has been a phenomenal success in identifying risk loci but not age-at-onset modifiers. We conducted a genome-wide study for age-at-onset. We analysed familial and non-familial PD separately, per prior evidence for strong genetic effect on age-at-onset in familial PD. GWAS was conducted in 431 unrelated PD individuals with at least one affected relative (familial PD) and 1544 non-familial PD from the NeuroGenetics Research Consortium (NGRC); an additional 737 familial PD and 2363 non-familial PD were used for replication. In familial PD, two signals were detected and replicated robustly: one mapped to LHFPL2 on 5q14.1 (PNGRC = 3E-8, PReplication = 2E-5, PNGRC + Replication = 1E-11), the second mapped to TPM1 on 15q22.2 (PNGRC = 8E-9, PReplication = 2E-4, PNGRC + Replication = 9E-11). The variants that were associated with accelerated onset had low frequencies (<0.02). The LHFPL2 variant was associated with earlier onset by 12.33 [95% CI: 6.2; 18.45] years in NGRC, 8.03 [2.95; 13.11] years in replication, and 9.79 [5.88; 13.70] years in the combined data. The TPM1 variant was associated with earlier onset by 15.30 [8.10; 22.49] years in NGRC, 9.29 [1.79; 16.79] years in replication, and 12.42 [7.23; 17.61] years in the combined data. Neither LHFPL2 nor TPM1 was associated with age-at-onset in non-familial PD. LHFPL2 (function unknown) is overexpressed in brain tumours. TPM1 encodes a highly conserved protein that regulates muscle contraction, and is a tumour-suppressor gene.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study / methods*
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Parkinson Disease / genetics*
  • Polymorphism, Single Nucleotide
  • Proteins / genetics*
  • Tropomyosin / genetics*


  • LHFPL2 protein, human
  • Membrane Proteins
  • Proteins
  • TPM1 protein, human
  • Tropomyosin