About 10 % of patients with Parkinson’s diesase (PD) report a positive family history.1 Large meta-analyses of genome-wide association studies (GWAS) have identified an increasing number of common risk-variants, yet these do not fully account for familial clustering in PD.2 A deeper understanding of the genetic profiles of individual patients, including cases of familial non-Mendelian PD, could have implications for prognosis and personalized therapy.
The cumulative burden of common GWAS variants has been associated with earlier PD onset3-5 and higher rates of motor and cognitive progression.6,7 Presuming that common risk loci contribute to familial clustering in non-Mendelian PD, one would expect cumulative genetic risk score (GRS) to be on average higher in patients with a positive family history. However, a recent study reported slower progression in patients with affected first degree relatives.8
To further explore the relationship between cumulative genetic risk, family history and age at onset in PD we generated a combined dataset from two Norwegian9,10 (Oslo and ParkWest) and four US11-14 (dbGAP phs000126.v1.p1, phs000089.v3.p2, phs000196.v2.p1 and PPMI) studies comprising a total of 4266 patients and calculated individual GRS. Methods and results are described in further detail in an online supplement. We found a significant, independent association of both lower GRS (p=5.7*10−8, beta=−0.92, SE=0.17) and positive family history (p=4.5*10−9,beta=2.25,SE=0.38) with higher age at onset in a linear regression model including sex, country and top five principal components as covariates. Next, we assessed association between GRS and family history by logistic regression, observing a significant association (p=0.00052, odds ratio 95% CI=1.05–1.19).
Taken together, the results indicate that familial PD is paradoxically associated with later age at onset, occuring not because of a lower GRS, but in spite of a higher GRS (Table 1). Consequently, one or more unknown mechanisms must be responsible for the observed association between family history and later age at onset. The previous report showing slower progression in familial cases is consistent with the notion of familial PD as paradoxically milder than what should be expected based on the genetic load.8
Table 1.
The relationship between genetic risk, age at onset and family history
| Genetic risk score quintile | ||||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | ||
| Mean age at onset | Negative family history | 60.6 | 58.2 | 57.7 | 57.6 | 57.3 |
| Positive family history | 61.9 | 61.1 | 61.1 | 59.8 | 59.4 | |
| Age at onset quintile | ||||||
| 1 | 2 | 3 | 4 | 5 | ||
| Mean genetic risk Z-score | Negative family history | 0.61 | 0.58 | 0.46 | 0.41 | 0.35 |
| Positive family history | 0.70 | 0.68 | 0.63 | 0.52 | 0.46 | |
The table shows mean age at onset across quintiles of genetic risk and vice versa, contrasting the groups of positive versus negative family history Parkinson’s disease patients. Higher genetic risk is consistently seen with earlier onset. Yet with similar genetic burden, patients with family history have higher age at onset. Given similar age at onset, patients with family history have higher genetic risk score.
“False negative” family history, where siblings will later go on to develop PD, will plausibly be more frequent in early onset cases, as their siblings will also be younger. If this mechanism was driving the results, however, the same form of bias should also tend to give higher GRS in the non-familial PD group, not lower as we observed here. We note as a limitation that the included substudies were heterogeneous with respect to age at onset and the proportion of patients with positive family history.
We can currently only speculate about possible explanations behind the intriguing paradox this study uncovered, yet we note that our observations might be compatible with a scenario where the genetic risk factors that contribute to familial clustering interact with normal aging, having a disproportionately stronger effect in older individuals. Further studies are needed to map out how genetic profile contributes to different aspects of PD phenotype in the individual patient, which could ultimately have implications for prognosis and treatment.
Supplementary Material
Acknowledgements
The authors thank all study participants and investigators who provided publicly available data. Lasse Pihlstrøm is supported by the Norwegian Health Association and Michael J. Fox Foundation. Mathias Toft is supported by the Research Council of Norway and the South-Eastern Norway Regional Health Authority. We thank Ole Andreassen and the DemGene consortium for genotyping of the Oslo cohort. Genotyping of the ParkWest cohort was supported by the Michael J. Fox Foundation and Biogen, for which the authors are thankful to Aaron Day-Williams. The Norwegian ParkWest study has received support from the Research Council of Norway (grant# 177966), the Western Norway Regional Health Authority (grant# 911218 and grant# 912014), and the Norwegian Parkinson Research Foundation. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000949–06. For up-to-date information on the Parkinson’s Progression Marker Initiative (PPMI) visit www.ppmi-info.org. PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners including AbbVie, Avid Radiopharmaceuticals, Biogen, BioLegend, Bristol-Myers Squibb, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Roche, Sanofi Genzyme, Servier, Takeda, Teva and UCB.
Funding sources: Lasse Pihlstrøm is supported by the Norwegian Health Association and Michael J. Fox Foundation. Mathias Toft is supported by the Research Council of Norway and the South-Eastern Norway Regional Health Authority. Genotyping of the ParkWest cohort was supported by the Michael J. Fox Foundation and Biogen. The Norwegian ParkWest study has received support from the Research Council of Norway (grant# 177966), the Western Norway Regional Health Authority (grant# 911218 and grant# 912014), and the Norwegian Parkinson Research Foundation. This work was supported in part by the Intramural Research Program, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000949–06.
Financial disclosures
Madeleine Kristiansen: None
Jodi Maple-Grødem: Grants from the Norwegian Parkinson Research Foundation.
Guido Alves: Grants from the Western Norway Regional Health Authority and the Norwegian Parkinson Research Foundation.
Sampath Arepalli: U.S. government employee
Dena G. Hernandez: U.S. government employee
Hirotaka Iwaki: Grant from Michael J Fox Foundation
Mike A. Nalls: Dr. Nalls reports and is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda MD, USA. He also consults for Ilumina Inc., the Michael J Fox Foundation and University of California Helathcare among others.
Andrew Singleton: U.S. government employee
Ole-Bjørn Tysnes: None
Mathias Toft: Grants from the Research Council of Norway, the South-Eastern Norway Regional Health Authority and Michael J Fox Foundation
Lasse Pihlstrøm: Grants from the Norwegian Health Association, the South-Eastern Norway Regional Health Authority, Michael J Fox Foundation and the Norwegian Parkinson Research Foundation
Footnotes
Conflicts of interest: The authors declare no conflict of interest.
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