Objective:

Genomic approaches  in Caucasian population show little transferability to other ethnically diverse populations such as Indian population. Understanding the genetic architecture of a disease requires capturing most of the genetic variations across different populations. 

Background: Genetic variability in the leucine rich repeat kinase 2 (LRRK2) gene is a common cause of familial and sporadic forms of Parkinson disease (PD) in Caucasians, African- Arabs, Ashkenazi Jews, and East Asians. The knowledge of the role of the LRRK2- dependent PD in the Indian population is lacking. 

Methods: We followed a two-stage design. First, we performed in-depth targeted resequencing of LRRK2 locus in 298 cases and 300 controls. Second, we used resequencing data to define the haplotypic structure of the LRRK2 locus. A Nextera rapid capture custom enrichment kit targeting 216 kbp of the LRRK2 locus including 5’ and 3’ untranslated region was used. The raw read data was analyzed using an in-house analysis pipeline: SeqPurge for adapter trimming, BWA mem for read mapping, samblaster for duplicate removal, ABRA for indel realignment, freebayes for variant calling and SnpEff/SnpSift for variant annotation. The hg19 genome was the reference

Results:

An average sequencing depth of 244x was achieved. On an average, 97.85% of the 216 kbp target region was covered at least 20x. 288 PD and 298 control samples were available for the variant analysis. Using strict filtering criteria, we identified ten novel missense variants in LRRK2 gene, not hitherto reported (ExAC, EVS, 1000 Genomes, and GME). The frequencies of novel variants vary from 0.001% to 0.003% indicating that these novel variants are a rare cause of PD in Indian population.  Resequencing  LRRK2 locus excluded G2019S, Asn1437His, Arg1441Cys, Arg1441Gly, Tyr1699Cys, Ile2020Thr. In contrast to rare missense variants, we identified a cluster of common markers (minor allele frequency>5%) which showed a trend for association with PD, suggesting that common genetic variability in the LRRK2 gene may be a risk factor for sporadic PD in Indian population.

Conclusions: The first ever in-depth comprehensive analyses of LRRK2 locus in Indian population revealed a distinct haplotypic structure. There are multiple haplotype blocks of LRRK2 in Indians when compared to the Caucasians. This emphasizes the need to diversify genetic research to identify causal variants for complex diseases

« Back to 2017 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/understanding-the-role-of-lrrk2-in-indian-population/