Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

Evolution of disability pension after renal transplantation: methods and results of a database linkage study of the Swiss Transplant Cohort Study and Swiss Disability Insurance.

In Switzerland, certain patients with disabilities and reduced working ability are entitled to a disability pension granted by the Swiss Federal Social Insurance Office (FSIO). The aim was to assess the evolution of disability pension and work capacity after kidney transplantation and thereby pilot the procedures linking FSIO data with Swiss Transplant Cohort Study (STCS) data. The current study pilot tested the record linkage of FSIO data with data from the STCS in a single-centre, observational setting. Patients were requested to consent to the use of their Swiss social security number (SSSN) for the purpose of record linkage. A privacy preserving trust centre approach was implemented with blinded statistical analysis. Between May 2008 and December 2015, 282 working-age renal transplant recipients of the University Hospital of Basel transplant centre were eligible for inclusion and 136 (48%, median age 48 years) consented to the use of their social security number and record linkage. The FSIO datasets of all patients were successfully retrieved and linked to STCS data in the trust centre and were numerically analysable. Yearly FSIO allowance data were available for the entire study duration. Fifty-five patients (40%) were registered as disability insurance recipients (DIR). In the entire population, the proportion of working patients slightly decreased from 76% to 72% between the pre-transplant and the post-transplant period. This was due to the lower proportion of patients working after transplantation in DIR compared with non-recipients (non-DIR) (DIR: 60% before vs 44% after; non-DIR: 83% before vs 88% after). In the DIR group, the proportion of patients not working increased from 36% to 49%, whereas in non-DIR the proportion changed only marginally (14% to 12%). The average disability insurance allowance was CHF 1172 per month. It changed from CHF 1135 before transplantation to CHF 1209 after transplantation (p = 0.59). In the Swiss healthcare and social insurance system, record linkage studies combining clinical datasets with data from FSIO are feasible but associated with great efforts and resource needs. The lack of changes in disability allowances after kidney transplantation should be further investigated in the nationwide setting

Parkin mutations and susceptibility alleles in late-onset Parkinson's disease

Parkin, an E2-dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late-onset form of Parkinson's disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early-onset and 2% of late-onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late-onset form of Parkinson disease

Association study of parkin gene polymorphisms with idiopathic Parkinson disease

Background Previously, we detected linkage of idiopathic Parkinson disease (PD) to the region on chromosome 6 that contains the Parkin gene (D6S305; logarithm of odds score, 5.47) in families with at least one individual with age at onset younger than 40 years (families with early-onset disease). Further study demonstrated the presence of Parkin mutations in this data set. However, previous case-control studies have reported conflicting results regarding the role of more common Parkin polymorphisms as susceptibility alleles for idiopathic PD. Objective To investigate the association of 7 previously studied Parkin single-nucleotide polymorphisms (SNPs) throughout the promoter and most of the open reading frame with PD in a large cohort of patients with primarily late-onset PD. Methods One promoter, 3 intronic, and 3 exonic Parkin SNPs were genotyped in 1580 individuals belonging to 397 families, and their association with PD was evaluated using family-based association tests. Results No significant association (P>.05) between PD and any Parkin SNP allele or genotype was detected. Haplotype analysis and stratification by age at onset or family history also failed to produce significant results. Conclusions These results suggest that these common variants of Parkin are not associated with PD in white patients, although Parkin mutations are known to cause early- and late-onset PD

The α-synuclein gene is not a major risk factor in familial Parkinson disease

Letter to the Edito

Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease

Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34–0.91; P=.02) or K (OR 0.52; 95% CI 0.30–0.90; P=.02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39–0.73; P=.0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27–0.71; P=.0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22–0.93; P=.03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression

Genetic polymorphisms of the N-acetyltransferase genes and risk of Parkinson's disease

Recently, the authors demonstrated linkage in idiopathic PD to a region on chromosome 8p that contains the N-acetyltransferase genes, NAT1 and NAT2. The authors examined NAT1 and NAT2 for association with PD using family-based association methods and single nucleotide polymorphisms (SNPs). The authors did not find evidence for association with increased risk for PD between any individual NAT1 or NAT2 SNP or acetylation haplotype (N = 397 families, 1,580 individuals)

Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease

CONTEXT The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. OBJECTIVE To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE Family-based tests of association, calculated using asymptotic distributions. RESULTS Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11). CONCLUSIONS This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD

Complete genomic screen in Parkinson Disease

Context The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. Objective To identify genetic risk factors for idiopathic PD. Design, Setting, and Participants Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. Main Outcome Measures Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. Results Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. Conclusions Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD. Parkinson disease (PD) is a neurodegenerative disease that affects more than a half-million people in the United States.1 The economic, social, and emotional burden of PD will increase as the population ages. Controversy has surrounded the etiology of PD, with evidence suggesting that both genetic and environmental factors influence disease risk. Familial aggregation of PD has been observed for decades.2 Data from family studies, including a recent large study from Iceland,3 have shown that the sibling recurrence risk ratio ranges from 2 to 10, suggesting that a genetic component to PD exists. However, twin studies4- 6 have produced conflicting results about the genetic contributions, suggesting that little if any genetic contribution exists in the development of PD. Previous efforts to identify genetic risk factors for PD have focused primarily on rare, simple autosomal dominant and recessive forms of the disease. Mutations in the α-synuclein gene, located on chromosome 4q, have been shown to be rare causes of autosomal dominant, early-onset PD.7 Mutations in the parkin gene, located on chromosome 6q, have been reported in families with rare autosomal recessive juvenile parkinsonism and autosomal recessive early-onset PD.8,9 Linkage of several large families with autosomal dominant PD to chromosome 2 has been reported,10 but a disease-causing gene remains to be identified. Collectively, these studies have demonstrated genetic effects only for rare single-gene variants of PD. To examine the broader issue of genetic effects in idiopathic PD, we performed a complete genomic screen for linkage analysis in 174 families with PD containing at least 1 affected relative pair