Complex segregation analysis of Parkinson's disease: The Mayo Clinic Family Study.

OBJECTIVE: To conduct complex segregation analyses of Parkinson's disease (PD). METHODS: Data on the familial aggregation of PD remain conflicting. We conducted a historical cohort study of 1,234 relatives of 162 patients with PD representative of people of Olmsted County, MN, and of 3,009 relatives of 411 patients with PD referred to the Mayo Clinic. Relatives were interviewed and screened for parkinsonism either directly or through a proxy, those who screened positive were examined, or a copy of their medical record was obtained to confirm the diagnosis. For subjects who resided in Olmsted County, additional information was obtained from the archives of the Olmsted County Historical Society and from a records-linkage system. RESULTS: Thirty-two relatives of population-based probands and 69 relatives of referral patients developed PD (101 in total). Combining population-based and referral samples, the model that best explained the familial clustering of PD overall was a major gene with additive effect on the penetrance. This model predicted an average decrease in age at onset of PD of approximately 18 years for each copy of the putative high-risk allele. The best fitting model for younger onset PD (age 59 years) were a recessive or an additive model. INTERPRETATION: The familial aggregation of PD may be explained in part by a major gene with additive effect on the penetrance.

Reliability of self-reported ancestry among siblings: implications for genetic association studies.

This study investigated the reliability of self-reported ancestry by comparing the interview responses of probands and their siblings. A total of 546 sibling pairs were ascertained in a family-based study of susceptibility genes for Parkinson's disease and asked to identify maternal and paternal countries of origin. Probands were recruited prospectively from the Department of Neurology of the Mayo Clinic in Rochester, Minnesota, from June 1, 1996, through May 31, 2005. Probands resided within Minnesota or one of the four surrounding states (Wisconsin, Iowa, South Dakota, North Dakota). Only 49 percent of these sibling pairs, primarily Caucasian, agreed completely on the countries of origin of both parents. The agreement increased to 68 percent when named countries were postcoded into six population genetic clusters (as previously defined by microsatellite markers). Self-reported ancestry may not be a reliable method to reduce the possible impact of population stratification in genetic association studies of outbred populations, such as in the United States.

High-resolution whole-genome association study of Parkinson disease.

We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P<.01 in tier 1) and 300 genomic control SNPs in 332 matched case-unrelated control pairs. We identified 11 SNPs that were associated with PD (P<.01) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined data from the case-unaffected sibling pair (tier 1) and case-unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P=7.62 x 10(-6)). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P=1.70 x 10(-5)). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P<.05) in tier 1 but that tested a priori biological and genetic hypotheses regarding susceptibility to PD (n=941 SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest P values (P=9.07 x 10(-6); P=2.96 x 10(-5)) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNPs in conferring PD susceptibility.

UCHL1 is associated with Parkinson's disease: a case-unaffected sibling and case-unrelated control study.

To avoid the possible confounding effect of population stratification, we employed a discordant sibling study design and a liberalization of the sibling transmission disequilibrium test to confirm the association of the S18Y variant of the ubiquitin carboxi-terminal hydrolase L1 (UCHL1) gene with Parkinson's disease (PD). The study included 497 case-control pairs (427 case-unaffected sibling pairs and 70 case-unrelated control pairs). Analyses confirmed a significant inverse association of the UCHL1 S18Y polymorphism with PD overall (OR=0.18, 95% CI=0.05-0.64, p=0.002, recessive model) and in several strata.

Interaction of alpha-synuclein and tau genotypes in Parkinson's disease.

To determine whether the microtubule-associated protein tau (MAPT) and alpha-synuclein (SNCA) genes interact to confer Parkinson's disease (PD) susceptibility, we conducted a study of 557 case-control pairs. There was an increased risk of PD for persons with either SNCA 261/261 or MAPT H1/H1 genotypes as compared with persons with neither (odds ratio, 1.96; 95% confidence interval, 1.34-2.86; p = 0.0003). However, the combined effect of the two genotypes was the same as for either of the genotypes alone (separate and equal). These findings are consistent with in vitro experiments that revealed tau-mediated fibrillization of alpha-synuclein protein at low concentrations (dose threshold effect).

Human brain derived neurotrophic factor (BDNF) genes, splicing patterns, and assessments of associations with substance abuse and Parkinson's Disease.

Potential roles for variants in the human BDNF gene in human brain disorders are supported by findings that include: (a) influences that this trophic factor can exert on important neurons, brain regions, and neurotransmitter systems, (b) changes in BDNF expression that follow altered neuronal activity and drug treatments, and (c) linkages or associations between genetic markers in or near BDNF and human traits and disorders that include depression, schizophrenia, addictions, and Parkinson's disease. We now report assembly of more than 70 kb of BDNF genomic sequence, delineation of 7 noncoding and 1 coding human BDNF exons, elucidation of BDNF transcripts that are initiated at several alternative promoters, identification of BDNF mRNA splicing patterns, elucidation of novel sequences that could contribute to activity-dependent BDNF mRNA transcription, targeting and/or translation, elucidation of tissue-specific and brain-region-specific use of the alternative human BDNF promoters and splicing patterns, identification of single nucleotide polymorphism (SNP), and simple sequence length polymorphism (SSLP) BDNF genomic variants and identification of patterns of restricted haplotype diversity at the BDNF locus. We also identified type 2 BDNF-locus transcripts that are coded by a novel gene that is overlapped with type 1 BDNF gene and transcribed in reverse orientation with several alternative splicing isoforms. Association studies of BDNF variants reveal no associations with Parkinson's disease. Comparisons between substance abusers and controls reveal modest associations. These findings increase interest in this diverse human gene.

Familial aggregation of Parkinson's disease: The Mayo Clinic family study.

Data on the familial aggregation of Parkinson's disease (PD) remain conflicting. We conducted a historical cohort study of 1,001 first-degree relatives of 162 probands with PD and of 851 relatives of 147 control probands representative of the population of Olmsted County, Minnesota (from 1976 through 1995). In addition, we studied 2,713 first-degree relatives of 411 probands with PD referred to the Mayo Clinic from 1996 through 2000 and 625 spouses of PD or control probands. Whenever possible, relatives were interviewed and screened for parkinsonism either directly or through a proxy, and those who screened positive were examined or a copy of their medical record was obtained to confirm the diagnosis (family study method). Thirty relatives of population-based PD probands, 18 relatives of population-based control probands, 65 relatives of referral PD probands, and 8 spouses had developed PD. Combining population-based with referral PD probands and population-based control probands with spouses, the relative risk was modestly increased (relative risk, 1.71; 95% confidence interval, 1.11-2.64). Relatives of probands with younger onset (