Whole-genome sequencing of 50 LRRK2 G2019S carriers discordant for Parkinsons disease. C. Y. McLean, E. Drabant, E. Harrington, C. B. Do, N. Eriksson 23andMe, Inc., Mountain View, CA.

   Parkinsons disease is a neurodegenerative disorder that affects over 6 million people worldwide. Over 20 SNPs have been associated with Parkinsons disease susceptibility. The most common known association is the LRRK2 G2019S mutation, with a population frequency ranging from under 1% in Asians to 40% in North African Arabs. G2019S is present in both familial autosomal dominant and sporadic Parkinsons disease and has an estimated penetrance of 30-100%. Higher penetrance estimates in familial cases suggest the presence of additional genetic or environmental penetrance modifiers. We performed whole-genome sequencing on 50 unrelated European individuals concordant for the presence of the LRRK2 G2019S mutation, the absence of the Parkinsons-associated GBA N370S and L444P mutations, and the absence of family history of Parkinsons disease. The cohort, drawn from consenting 23andMe customers, comprises 50 individuals: 37 affected by Parkinsons disease and 13 healthy controls. The median age of onset for affected individuals is 56 (range 38-85). The median age of healthy controls is 66 (range 58-95). Whole-genome sequencing was performed on DNA extracted from bio-banked saliva samples. Individuals were sequenced to a median mapped depth of 45-fold coverage (range 34-52), spanning a median of 97.9% of the genome (range 97.8-98.2%). Mutational burden was similar in cases and controls: a median of 3.59M SNPs and 599k indels arise per genome, in agreement with previous estimates of individual human variation. Concordance between mutations identified by whole-genome sequencing and chip genotyping exceeds 99.7% for all samples. Premature stop codon mutations occur in a median of 96 genes (range 81-114). This study demonstrates the power of the innovative 23andMe customer database for generating research cohorts of interest, confirms the feasibility of generating accurate whole-genome sequencing data from saliva, and provides a rich data set that may help identify genomic differences between LRRK2 G2019S carriers discordant for Parkinsons disease.

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