Search

The objective of this study was to investigate the association between a Parkinson's disease (PD)-specific polygenic score (PGS) and protective lifestyle factors on age at onset (AAO) in PD. We included data from 4367 patients with idiopathic PD, 159 patients with GBA1-PD, and 3090 healthy controls of European ancestry from AMP-PD, PPMI, and Fox Insight cohorts. The association between PGS and lifestyle factors on AAO was assessed with linear and Cox proportional hazards models. The PGS showed a negative association with AAO (β = - 1.07, p = 6 × 10 -7 ) in patients with idiopathic PD. The use of one, two, or three of the protective lifestyle factors showed a reduction in the hazard ratio by 21% (p = 0.0001), 44% (p < 2 × 10 -16 ), and 55% (p < 2 × 10 -16 ), compared to no use. An additive effect of aspirin (β = 7.62, p = 9 × 10 -7 ) and PGS (β = - 1.58, p = 0.0149) was found for AAO without an interaction (p = 0.9993) in the linear regressions, and similar effects were seen for tobacco. In contrast, no association between aspirin intake and AAO was found in GBA1-PD (p > 0.05). In our cohort, coffee, tobacco, aspirin, and PGS are independent predictors of PD AAO. Additionally, lifestyle factors seem to have a greater influence on AAO than common genetic risk variants with aspirin presenting the largest effect., (© 2024. The Author(s).)

Pigs (Sus scrofa) were first domesticated between 8,500 and 8,000 cal BC in the Near East, from where they were subsequently brought into Europe by agriculturalists. Soon after the arrival of the first domestic pigs in northern Europe (~4500 BC), farmers are thought to have started to incorporate local wild boars into their swine herds. This husbandry strategy ultimately resulted in the domestication of European wild boars. Here, we set out to provide a more precise geographic and temporal framework of the early management of suid populations in northern Europe, drawing upon mitochondrial DNA haplotype data from 116 Neolithic Sus specimens. We developed a quantitative mathematical model tracing the haplotypes of the domestic pigs back to their most likely geographic origin. Our modelling results suggest that, between 5000 and 4000 BC, almost all matrilines in the north originated from domesticated animals from the south of central Europe. In the following period (4000-3000 BC), an estimated 78-100% of domesticates in the north were of northern matrilineal origin, largely from local wild boars. These findings point towards a dramatic change in suid management strategies taking place throughout south-central and northern Europe after 4000 BC.

Human pigmentation traits are of great interest to many research areas, from ancient DNA analysis to forensic science. We developed a gene-based predictive model for pigmentation phenotypes in a realistic target population for forensic case work from Northern Germany and compared our model with those brought forth by previous studies of genetically more heterogeneous populations. In doing so, we aimed at answering the following research questions: (1) do existing models allow good prediction of high-quality phenotypes in a genetically similar albeit more homogeneous population? (2) Would a model specifically set up for the more homogeneous population perform notably better than existing models? (3) Can the number of markers included in existing models be reduced without compromising their predictive capability in the more homogenous population? We investigated the association between eye, hair and skin colour and 12 candidate single-nucleotide polymorphisms (SNPs) from six genes. Our study comprised two samples of 300 and 100 individuals from Northern Germany. SNP rs12913832 in HERC2 was found to be strongly associated with blue eye colour (odds ratio=40.0, P<1.2 × 10(-4)) and to yield moderate predictive power (AUC: 77%; sensitivity: 90%, specificity: 63%, both at a 0.5 threshold for blue eye colour probability). SNP associations with hair and skin colour were weaker and genotypes less predictive. A comparison with two recently published sets of markers to predict eye and hair colour revealed that the consideration of additional SNPs with weak-to-moderate effect increased the predictive power for eye colour, but not for hair colour.

Our study demonstrates that the genetic investigation of forkhead box O3A gene (FOXO3A), a validated human longevity gene, is greatly hampered by the fact that its exonic regions have 99% sequence homology with the FOXO3B pseudogene. If unaccounted for, this high degree of homology can cause serious genotyping or sequencing errors. Here, we present an experimental set-up that allows reliable data generation for the highly homologous regions and that can be used for the evaluation of assay specificity. Using this design, we exemplarily showed FOXO3A-specific results for two single-nucleotide polymorphisms (SNPs) (rs4945816 and rs4946936) that are significantly associated with longevity in our centenarian-control sample (P(each)=0.0008). Because both SNPs are located in the 3' untranslated region of FOXO3A, they could be of functional relevance for the longevity phenotype. Our experimental set-up can be used for reliable and reproducible data generation for further sequencing and genotyping studies of FOXO3A with the aim of discovering new SNPs of functional relevance.

The gene tyrosine hydroxylase 1 (TH01) has been suggested as a candidate for human longevity. A previous study has shown an association between longevity and specific alleles of the TH01 short tandem repeat (STR) polymorphism in an Italian population. This STR locus is also widely used in forensic genetics. If the TH01-longevity association could be confirmed in independent samples, this finding would have important ramifications for the use of this polymorphism in a forensic context. In the present study, we sought to replicate the previous association result by investigating 471 long-lived individuals (96-110 years) and 462 younger controls (19-75 years) from Germany. In the analyzed samples, the association between TH01 and longevity was not replicated. However, the obtained TH01 allele frequencies were consistent with published data. We observed considerable differences in the allele distribution between Germans and Italians, in particular with regard to allele 9.3, which displayed a previously undetected decreasing West-East and North-South cline across Europe. The discrepant TH01-longevity association results in Germans and Italians could therefore be due to population-specific effects. This finding highlights the need to take into consideration population genetic data when dealing with association studies.

Risk alleles for age-related diseases are expected to decrease in frequency in the population strata of increasing age. Consistent with this hypothesis, earlier studies showed a depletion of the Alzheimer's disease risk factor APOE*epsilon4 in long-lived individuals (LLIs). To evaluate whether this observation also holds for a previously suggested Alzheimer's disease risk haplotype in the A2M gene, we analyzed this particular haplotype in 1042 German LLIs (aged 95-100 years) and 1040 younger individuals (aged 60-75 years). Our results show a significant depletion of this haplotype in LLIs, thus confirming it as a mortality factor in the elderly. Consequently, our data support an involvement of the suggested A2M risk haplotype in the pathogenesis of Alzheimer's disease and adds new evidence to the risk-allele depletion hypothesis.

Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene-disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309,790 markers; Affymetrix GeneChip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given individual, based on the IBS status for the subset alone. However, our results suggest that, by following this approach, the prediction accuracy is only notably improved by the first 20 markers selected, and increases proportionally to the marker number thereafter. Furthermore, in a considerable proportion of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable of predicting the BOM than randomly chosen subsets. This leads us to conclude that, at least in Europe, the utility of the genetic-matched pair study design depends critically on the availability of comprehensive genotype information for both cases and controls.