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

Abstract

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.

Parkinson's disease susceptibility variants and severity of Lewy body pathology

“…The relatively subtle association between SNCA rs3910105 and LB counts in one of the five studied brain regions in our study suggests that although common SNCA variation could play a limited role in the degree to which LB pathology progresses after it initially develops, it is likely more involved in the initial appearance of the pathology. Interestingly, SNCA variants (and PD risk variants in general) have also not been observed to strongly associate with clinical features such as age-at-onset as may be expected given findings from SNCA multiplication families [21–23]. The MAPT H1 haplotype, another very well-replicated risk factor for PD, has been inconsistently associated with severity of LB pathology [7–9].…”

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

“…Mutations in a series of primary genes are known to cause autosomal dominant and recessive forms of PD [28,29,30,31,32,33,34,35,36,37,38]. Mutations in some genes—e.g., α-Synuclein ( SNCA ), Parkin 2 ( PARK2 ), PTEN-induced putative kinase 1 ( PINK1 ), PARK7 , Leucine-rich repeat kinase 2 ( LRRK2 ), Bone narrow stromal cell antigen 1 ( BST1 ), Microtubule-associated protein tau ( MAPT )—might be causative in familial forms of PD whereas diverse genetic defects in other loci might represent susceptibility loci associated with sporadic PD without family history [28,34,35,36,37,38,39].…”

“…Mutations in some genes—e.g., α-Synuclein ( SNCA ), Parkin 2 ( PARK2 ), PTEN-induced putative kinase 1 ( PINK1 ), PARK7 , Leucine-rich repeat kinase 2 ( LRRK2 ), Bone narrow stromal cell antigen 1 ( BST1 ), Microtubule-associated protein tau ( MAPT )—might be causative in familial forms of PD whereas diverse genetic defects in other loci might represent susceptibility loci associated with sporadic PD without family history [28,34,35,36,37,38,39]. Mendelian variants with high penetrance (e.g., SNCA , LRRK2 , PINK1 , PARK7 genes) explain less than 10% of familial PD [40].…”

Biochemical Changes and Cardiovascular Function in Parkinson ’s Disease: Precautionary Notes

“…Different genes distributed across the human genome have been associated with PD, including GBA, ADH1C, TBP SCA17, HDL4, ATXN2, MAPT, SNCA, PARK1-22, LRRK2, PINK1, CHCHD2, UCHL1, APOE, and many others [10,11]. All these genes are under the influence of the epigenetic machinery (DNA methylation, chromatin remodeling, histone modifications, miRNAs) that regulates their expression in different tissues and may contribute to selective nigrostriatal dopaminergic neurodegeneration.…”

“…Furthermore, gastrointestinal complications (constipation, sialorrhea, dysphagia, difficulty in mastication, choking/aspiration) [23], cardiovascular problems [24], neuroendocrine changes and psychiatric disorders are frequent in Parkinsonian patients chronically treated with conventional antiparkinsonian drugs [16,23]. The onset of these complications is also influenced by the genomic background of the patients [11]; and the efficacy and safety of the drugs currently consumed by those who suffer a Parkinsonian disorder is highly dependent on their pharmacogenomic profile [25][26][27][28][29]. Genes involved in the pharmacogenetic network include pathogenic, mechanistic, metabolic, transporter and pleiotropic genes, and all these genes are also under the influence of potential epigenetic aberrations [30][31][32].…”