Geiger, JT;
Ding, J;
Crain, B;
Pletnikova, O;
Letson, C;
Dawson, TM;
Rosenthal, LS;
... Scholz, SW; + view all
(2016)
Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies.
Neurobiology of Disease
, 94
pp. 55-62.
10.1016/j.nbd.2016.06.004.
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Abstract
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~ 25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value < 0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia.
| Type: | Article |
|---|---|
| Title: | Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.nbd.2016.06.004 |
| Publisher version: | http://dx.doi.org/10.1016/j.nbd.2016.06.004 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, Dementia with Lewy bodies, Exome sequencing, Alzheimer dementia, Lewy body dementia, GBA, PSEN1, APP, APOE, AMYLOID PRECURSOR PROTEIN, ONSET ALZHEIMERS-DISEASE, PARKINSONS-DISEASE, GAUCHER-DISEASE, GLUCOCEREBROSIDASE MUTATIONS, BODY DISEASE, ASSOCIATION, VARIANT, RISK |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10048690 |
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