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of levodopa dose. Results of clinical studies, however, indicate that COMT
genotype seems to be a minor factor in judging the benefi cial effects of entacapone
administration. If gene polymorphisms that affect the metabolism of antiparkinso-
nian drugs can be identifi ed, it might assist physicians in prescribing the drug dose
that will balance short-term control of tremors with long-term drug side effects that
eventually render PD untreatable.
Results of the largest case-control genome-wide association study so far indicate
a substantial contribution of genetics to susceptibility for both early-onset and late-
onset PD, although most of the genetic components of this disease remain to be
discovered (Do et al. 2011 ). Understanding of the genomics of PD has been
improved by application of molecular methods. Five genes are now known to cause
monogenic forms of PD and these were identifi ed using genetic linkage approaches,
which require large pedigrees with affected as well as unaffected individuals. Two
of these genes, SNCA and LRRK2, cause dominant forms of PD, while mutations
inPARK2, PINK1 and DJ-1 were shown to underlie recessive forms of the disease.
Eleven loci were identifi ed as risk factors for the development of common forms of
PD (Plagnol et al. 2011 ). However, a signifi cant proportion of inherited cases of PD
still remain unexplained genetically and the cause of the disease remains somewhat
elusive. Currently, there is no diagnostic test that can confi rm PD. Diagnosis is usu-
ally made by clinical observation and confi rmed only post-mortem by neuropatho-
logical studies.
Exome sequencing has now been applied to PD research and has the potential for
use as a screening method to identify pathogenic mutations in some PD patients
(Bras and Singleton 2011 ). A major challenge of exome sequencing is the amount
of data generated, and the rapid evolution of methods to evaluate these data.
Members of the International Parkinson’s Disease Genomics Consortium have
used whole exome sequencing (WES) as part of their ongoing search for new
genetic contributors to neurodegenerative disease. In 2013, scientists at VU
University Medical Center in the Netherlands outlined their efforts and fi ndings. By
sequencing and comparing the exomes of individuals with familial or sporadic PD
and unaffected controls, they identifi ed common variants, rare variants, and combi-
nations of the two that contribute to risk of PD. They found that over-representation
of genes from three inter-connected pathways contribute to mitophagy, autophagy,
and endocytosis-related processes. The results indicate that dysfunctions affecting
those pathways may contribute to development of PD rather than being a conse-
quence of it. The researchers plan to do array-based profi ling on more PD patients
using the NeuroX exome chip to verify genetic results from the current exome
sequencing study. Consortium members are also in the process of resequencing
apparent PD loci detected through past studies of the condition. The team’s analysis
of common variant contributors to PD pointed to SNPs at >30 loci, while gene-
based association tests highlighted 169 genes with potential PD contributions. The
group continues to look for new genetic contributors to PD, while attempting to
verify candidate associations from the exome sequencing study using lab models
such as Caenorhabditis elegans and Drosophila as well as cell cultures generated
from human neuronal cells.
12 Personalized Management of Neurological Disorders