15 Aug 2017
Genetic forces drive a sizable portion of Alzheimers disease, yet only a fraction of cases thus far are explained by known mutations. A handful of recent papers used genomic sequencing to fish out new variants that, while exceedingly rare, pack a wallop in those who carry them. In the July 24 JAMA Neurology, researchers led by Margaret Pericak-Vance at the University of Miami in Florida reported that mutations in four endolysosomal transport genes boosted risk of early onset AD (EOAD). A few weeks earlier, a large collaboration of French researchers reported rare new TREM2, ABCA7, and SORL1 variants in Neurobiology of Aging, while scientists led by Henne Holstege at VU University Medical Center in Amsterdam characterized the pathogenicity of SORL1 variants and even proposed classifying this endosomal sorting protein as the fourth autosomal-dominant AD gene. A team led by Dominique Campion at University of Rouen, France, dug deep into the well-trodden territory of the three autosomal-dominant genesAPP, PS1, and PS2and uncovered de novo pathogenic variants that cropped up in people with no family history of AD. Last but not least, Anne Rovelet-Lecrux, also at Rouen, linked a duplication in the tau gene to people with an AD diagnosis who lacked Aplaques.
Together, the studies move the field a step closer to filling in the missing genetic influence on AD, and could provide new targets for therapeutic strategies, commented Liana Apostolova at the University of Indiana in Bloomington. There are more genetic risk factors in hiding that have yet to be discovered, and these studies suggest were on the right track, she toldAlzforum.
In the JAMA Neurology study, first author Brian Kunkle and colleagues report on their search for rare variants with large effects on AD risk. Reasoning that people with EOAD are likely carriers of damaging genetic mutations, they conducted whole-exome sequencing in 51 non-Hispanic white EOAD patients, plus 53 people from 19 Caribbean Hispanic families with EOAD; all had tested negative for known causal mutations in APP, PS1, and PS2. The scientists combed the exomes for variants predicted to have damaging effects, then attempted to validate each variants association with AD using exome genotyping data from a separate cohort of 1,500 EOAD patients, 7,000 LOAD patients, and 7,000 controls. Developed by the Alzheimers Disease Genetics Consortium (ADGC), the exome chip used to genotype this separate cohort contains more than 200,000 variants, most of which are functional, rare, single nucleotidemutations.
In their original sequencing cohort, the researchers identified mutations in known or suspected EOAD genes, including SORL1, PS1, PS2, TREM2, and MAPT. Some were known; others were new variants in genes previously tied to LOAD, including HLA-DRB1, ABCA7, and RIN3. Suspicious mutations also cropped up in genes without an AD record. A missense mutation in TCIRG1, present in a non-Hispanic white person with EOAD and segregating with EOAD in three Hispanic families, was twice as frequent in EOAD than in controls in the validation cohort. Deleterious mutations in PSD2 appeared in multiple unrelated cases in the sequencing cohort, and associated with EOAD in the validation cohort, at least when considered in the aggregate. Mutations in RIN3 and RUFY1 appeared in the discovery cohort, but their EOAD association in the validation group was nominal. Importantly, all four genes function in different parts of the endolysosomal transport pathway, which is essential for clearing cellular debris and unwanted proteins, includingA.
The researchers found additional rare mutations in EOAD patients, but these were not on the exome chip used for the validation cohort. For example, of 151 potentially damaging variants that appeared in the original exome sequencing cohort, only 43 were included on the exomechip.
While this filtering process allows researchers to test whether a variant is truly linked to disease, it also precludes consideration of totally new, potentially damaging mutations, said Holstege. The mutations that are most damaging are also the most rare, Holstege told Alzforum. If you filter them out in this way, you quench yoursignal.
Holstege took a different tack to find and classify rare SORL1 variants. Rather than filtering out undocumented variants, Holstege and colleagues made them their bread and butter. In the May 24 European Journal of Human Genetics, they reported 115 SORL1 variants from the exomes of a Dutch cohort of 640 AD cases and 1,268 controls. Fifteen of these variants were common, and not associated with AD. The other 100 were rare, occurring in less than 0.01 percent of the population. Of those, 19 were predicted to be strongly damaging, based on high scores on CADD, an algorithm that considers more than 100 variant characteristics to predict how likely a given mutation is to alter protein function orexpression.
Strikingly, 16 of these suspicious variants only appeared in a single person within the entire cohort, and 14 of those had AD. None of the variants were included in prior exome genotyping studies, so the researchers could not draw upon past data to validate whether they truly associated with the disease. Instead, the researchers developed a pathogenicity scale. Weaving in data from more than 3,000 exomes sequenced separately, the researchers classified a total 181 SORL1 variants based on their combined CADD scores and rarity. They categorized those that had high CADD scores and were very rare as pathogenic. Estimated pathogenicity decreased from likely pathogenic to uncertain to likely benign to benign as variants became less damaging and morecommon.
The scientists found that a combination of high CADD scores and extremely low allele frequency selected out those SORL1 variants that occurred much more often in cases than in controls. The 13 variants with the highest pathogenicity resulted in truncations of SORL1, and occurred only in AD cases. The researchers predicted they would cause dominantly inherited AD, though none have yet been traced in familypedigrees.
Holstege and colleagues proposed that SORL1 take a spot alongside PS1, PS2, and APP as an autosomal-dominant AD gene. Pathogenic SORL1 mutations occurred in 2 percent of the AD cases in this study, placing them at a higher frequency than other ADAD genes. Like PS1, PS2, and APP, SORL1 protein strongly influences A, as it protects APP from amyloidogenic processing and ushers A to lysosomes for disposal (see Sep 2007 news; Feb 2014 news).
Classifying SORL1 as an ADAD gene would raise new questions. How to provide genetic counseling to affected families? Should mutation carriers be eligible to join the Dominantly Inherited Alzheimers Network (DIAN)? Clinical-grade genetic tests for SORL1 variants would be needed, a challenge developers may postpone until further data has confirmed the mutations are pathogenic, commented Apostolova. She added that while Holsteges pathogenicity scale is an exciting tool that should be used in future studies, validation of each mutation in other cohorts, as well as functional evidence in animal and cell culture studies, should be required to elevate SORL1 to ADAD status. Rovelet-Lecrux agreed that designating SORL1 an ADAD gene will have to await discovery of multigenerational families in which SORL1 segregates with disease in an autosomal-dominant pattern. Until we accumulate more genetic evidence, we cannot tell SORL1 mutation carriers how likely they are to develop disease, shesaid.
A new study led by Rouens Campion and co-authored by Rovelet-Lecrux further supports pathogenicity of SORL1 variants, even if it does not provide evidence of multigenerational segregation. As reported July 13 in the Neurobiology of Aging, the researchers detected SORL1 missense and protein-truncating variants that associated strongly with early onset disease by doing whole-exome and genome sequencing of a French cohort of 852 EOAD, 927 LOAD, and 1,273 control cases. All but one of 13 protein-truncating variants occurred only in EOAD cases, and eight of 10 cases with available family information had a history of the disease. Besides SORL1, TREM2 and ABCA7 also harbored potentially damaging EOAD-associated variants in this sample. The researchers estimated that variants in these three genes accounted for 1.42, 1.17, and 1.33 percent of EOAD heritability, respectively. By comparison, ApoE4 accounted for 9.12percent.
New Finds in Old Genes While many pathogenic mutations in PS1, PS2, and APP have been traced in family pedigrees, additional rare variants in these established ADAD genes may yet be discovered. In search of them, researchers led by Rouens Campion sequenced these genes in 129 sporadic cases of early onset AD, as well as in 53 affected families. Published March 28 in PLOS Medicine, the findings included data from participants who joined the ongoing French study after 2012, when the researchers had published a similar analysis (Wallon et al., 2012).In all, first author Hlne-Marie Lanoisele and colleagues identified 44 PS1, two PS2, and 20 APP mutations, as well as five APP duplications; 12 of the PS1 and one PS2 mutation had not been reportedpreviously.
The most striking finding was the existence of de novo mutations in PS1. Indeed, seven of 12 new mutations occurred in sporadic cases of EOAD. In three of these mutations, the researchers were able to confirm that the carriers parents did not carry the new mutation. Rovelet-Lecrux, a co-author on the paper, said that the prevalence of de novo mutations in ADAD genes is likely underestimated, because routine genetic screening for these mutations is done only in familial AD cases. The de novo find underscores the importance of checking for pathogenic mutations even in patients without a family history of AD, especially people with an early age at onset, Holstege commented. Similar to the situation with rare SORL1 variants, researchers will need to decide how to categorize carriers of new and de novo mutations in established ADAD genes, shesaid.
Finally, results from a slightly older study led by Rovelet-Lecrux pose a different kind of classification conundrum. The authors deployed whole-exome sequencing to hunt specifically for copy number variations (CNVs) such as duplications and deletions in 335 genes predicted to influence A processing, clearance, or aggregation. The researchers found CNVs in 30 out of 522 people with EOAD, but only 18 out of 584 controls. Most of these CNVs occurred in a single person in the cohort, and they included novel deletions in the PS1, ABCA7, and SLC30A3 genes previously tied toAD.
A surprising finding reared its head in four AD cases, who all had a duplicationin a region of chromosome 17 including MAPT, the gene encoding none other than tau. The duplication appeared in two sporadic cases of EOAD and two with a family history. DNA available from one of those families confirmed that the duplication segregated with EOAD. Even though these four carriers had symptoms consistent with AD, the three who underwent amyloid-PET imaging had negative scans, to Rovelet-Lecruxs surprise. All four duplication carriers had abnormal levels of CSF p-tau and tau, and three of them also had abnormal concentrations of A42. The researchers also found nearly double the amount of tau mRNA in the blood of carriers than incontrols.
Together, the findings suggest that despite the lack of A plaques visible on PET, carriers of a tau duplication have a clinical disorder markedly similar to AD. The abnormality of CSF A42 in three of the duplication carriers suggests that they could have accumulated A just below the level of PET detection, a sub-threshold aggregation the researchers speculated could even be somehow caused by elevatedtau.
Do these tau duplication carriers have AD? Not if you consider A accumulation as a defining feature of the disease, said Apostolova. Indeed, in the paper, the researchers defined their disease as a tau-related dementia, proposing that it could account for a significant proportion of early onset dementia cases with no genetic explanation. While some researchers view A as a mere forerunner to the more destructive tau pathology, which they consider the main event in AD, Rovelet-Lecrux shied away from separating A from AD, saying that AD is ultimately diagnosed via its neuropathological hallmarks of A plaques and tau tangles. She believes it will be important to screen EOAD patients without A plaques for tau pathology, especially in the future once both A- or tau-targeted therapies exist.JessicaShugart
No Available Comments
To make a comment you must login or register.
Continue reading here:
The Search for the Missing AD Heritability Turns Up New Rare Variants - Alzforum
- Copy number variation of the restorer Rf4 underlies human selection ... - Nature.com - November 15th, 2023 [November 15th, 2023]
- NYU Langone Health in the NewsThursday, November 9, 2023 - NYU Langone Health - November 15th, 2023 [November 15th, 2023]
- Eugenics: Plaguing scientific community with dark history | Opinion ... - The Arkansas Traveler - November 15th, 2023 [November 15th, 2023]
- Cranberries can bounce, float and pollinate themselves: The saucy ... - Japan Today - November 15th, 2023 [November 15th, 2023]
- Government Housing Assistance Linked to Increased Cancer ... - HealthDay - November 15th, 2023 [November 15th, 2023]
- Rate of New Lung Cancer Cases Has Decreased Over Last Five Years - HealthDay - November 15th, 2023 [November 15th, 2023]
- Clinically relevant antibiotic resistance genes are linked to a limited ... - Nature.com - November 15th, 2023 [November 15th, 2023]
- Disparities in Guideline-Concordant Care Found for Black CRC ... - HealthDay - November 15th, 2023 [November 15th, 2023]
- Mathematician Heather Harrington is new director at the Max Planck ... - EurekAlert - November 15th, 2023 [November 15th, 2023]
- New study finds genetic testing can effectively identify patients with ... - EurekAlert - November 15th, 2023 [November 15th, 2023]
- STK11 loss leads to YAP1-mediated transcriptional activation in ... - Nature.com - November 15th, 2023 [November 15th, 2023]
- CRISPR-broad: combined design of multi-targeting gRNAs and ... - Nature.com - November 15th, 2023 [November 15th, 2023]
- Master regulator of the dark genome greatly improves cancer T-cell ... - Science Daily - November 15th, 2023 [November 15th, 2023]
- Omega Therapeutics Showcases Bidirectional and Multiplexed ... - BioSpace - November 15th, 2023 [November 15th, 2023]
- Today is International 15q Day - ASBMB Today - November 15th, 2023 [November 15th, 2023]
- Evolution of taste: Sharks were already able to perceive bitter ... - EurekAlert - November 15th, 2023 [November 15th, 2023]
- Stanford Scientists Uncover New Indicators of Health, Disease, and ... - SciTechDaily - October 16th, 2023 [October 16th, 2023]
- NHGRI Director Eric Green elected to the National Academy of ... - National Human Genome Research Institute - October 16th, 2023 [October 16th, 2023]
- Monkey survives for two years after gene-edited pig-kidney transplant - Nature.com - October 16th, 2023 [October 16th, 2023]
- Opinion: Interest in RNA Editing Accelerates as Therapies Approach ... - BioSpace - October 16th, 2023 [October 16th, 2023]
- Regulation of dermal fibroblasts by human neutrophil peptides ... - Nature.com - October 16th, 2023 [October 16th, 2023]
- Consistent effects of the genetics of happiness across the lifespan ... - Nature.com - October 16th, 2023 [October 16th, 2023]
- Storytelling through the looking glass of genetics The Stute - The Stute - October 16th, 2023 [October 16th, 2023]
- Pet dogs shed light on human health, researchers say - UPI News - October 16th, 2023 [October 16th, 2023]
- Native microbiome dominates over host factors in shaping the ... - Nature.com - October 16th, 2023 [October 16th, 2023]
- Illinois-led project to sequence soybean genomes, improve future ... - Herald-Whig - October 16th, 2023 [October 16th, 2023]
- Unrealized targets in the discovery of antibiotics for Gram-negative ... - Nature.com - October 16th, 2023 [October 16th, 2023]
- How Biotech And AI Are Transforming The Human - Noema Magazine - October 16th, 2023 [October 16th, 2023]
- The Many Lives of Alexandria Forbes - BioSpace - October 16th, 2023 [October 16th, 2023]
- CEP20 promotes invasion and metastasis of non-small cell lung ... - Nature.com - October 16th, 2023 [October 16th, 2023]
- Genotyping, sequencing and analysis of 140,000 adults from Mexico ... - Nature.com - October 16th, 2023 [October 16th, 2023]
- The role and impact of alternative polyadenylation and miRNA ... - Nature.com - October 16th, 2023 [October 16th, 2023]
- Human - Simple English Wikipedia, the free encyclopedia - January 30th, 2023 [January 30th, 2023]
- Deep Dive Ties Together Dog Genetics, Brain Physiology and Behavior to Explain Why Collies Are Different from Terriers - Scientific American - December 12th, 2022 [December 12th, 2022]
- How oxytocin drives connections of newly integrated adult-born neurons: Research - Hindustan Times - December 12th, 2022 [December 12th, 2022]
- Alzheimer's Disease Genetics Fact Sheet - National Institute on Aging - December 2nd, 2022 [December 2nd, 2022]
- Human genetic clustering - Wikipedia - November 23rd, 2022 [November 23rd, 2022]
- Human Genome Project Fact Sheet - November 23rd, 2022 [November 23rd, 2022]
- Abstracts | International Congress of Human Genetics 2023 - November 23rd, 2022 [November 23rd, 2022]
- Ancient DNA and Neanderthals | The Smithsonian Institution's Human ... - November 16th, 2022 [November 16th, 2022]
- Biological Influences on Human Behavior: Genetics & Environment - November 16th, 2022 [November 16th, 2022]
- Fluent BioSciences showcasing breakthrough solutions to enable unprecedented scale, cost-efficiency and access for single-cell RNA sequencing at the... - October 28th, 2022 [October 28th, 2022]
- Human behaviour genetics - Wikipedia - October 23rd, 2022 [October 23rd, 2022]
- Nucleome Therapeutics raises oversubscribed 37.5 million Series A financing to decode the dark matter of the human genome and deliver first-in-class... - October 19th, 2022 [October 19th, 2022]
- Gladstone data scientist elected to the National Academy of Medicine - EurekAlert - October 19th, 2022 [October 19th, 2022]
- Ocugen to Host R&D Day in New York City on Tuesday, November 1, 2022 - Yahoo Finance - October 19th, 2022 [October 19th, 2022]
- Pharmacy researcher earns $2.3 million NIH award to study opioid addiction - EurekAlert - October 19th, 2022 [October 19th, 2022]
- Study shows age often plays a bigger role than genetics in gene expression and susceptibility to disease - Anti Aging News - October 19th, 2022 [October 19th, 2022]
- CSRWire - Direct Relief, Amgen and C/Can Team Up To Improve Access to Breast Cancer Diagnostics and Treatment in Paraguay - CSRwire.com - October 19th, 2022 [October 19th, 2022]
- Maze Therapeutics Appoints Harold Bernstein, M.D., Ph.D., as President, Research and Development and Chief Medical Officer - Business Wire - October 19th, 2022 [October 19th, 2022]
- New Rare Disease Therapy Effectively Lowers Plasma Phe in Patients with PKU - MD Magazine - October 19th, 2022 [October 19th, 2022]
- GSK : announces expanded collaboration with Tempus in precision medicine to accelerate R&D - Marketscreener.com - October 19th, 2022 [October 19th, 2022]
- Famous Scientific Discoveries That Changed the Course of History - 24/7 Wall St. - October 19th, 2022 [October 19th, 2022]
- Construction workers seek fulfilment of their demands - Star of Mysore - October 19th, 2022 [October 19th, 2022]
- Genetics | The Smithsonian Institution's Human Origins Program - October 13th, 2022 [October 13th, 2022]
- Genetics - Wikipedia - October 13th, 2022 [October 13th, 2022]
- Study looking at human genetics and Covid vaccine immune responses - Science Media Centre - October 13th, 2022 [October 13th, 2022]
- ASHG 2022 in Los Angeles brings together researchers from around the world to advance discoveries in genetics, genomics research - EurekAlert - October 13th, 2022 [October 13th, 2022]
- Maze Therapeutics Appoints Harold Bernstein, M.D., Ph.D., as President, Research and Development and Chief Medical Officer - Yahoo Finance - October 13th, 2022 [October 13th, 2022]
- The Age of the Pangenome Dawns - DNA Science - PLOS - October 13th, 2022 [October 13th, 2022]
- Influence of the microbiome, diet and genetics on inter-individual variation in the human plasma metabolome - Nature.com - October 13th, 2022 [October 13th, 2022]
- Genome editing technologies: final conclusions of the re-examination of Article 13 of the Oviedo Convention - Council of Europe - October 13th, 2022 [October 13th, 2022]
- Global Biobank Meta-analysis Initiative making genome-wide association studies more diverse and representative - EurekAlert - October 13th, 2022 [October 13th, 2022]
- New NHS genetic testing service could save thousands of children in England - The Guardian - October 13th, 2022 [October 13th, 2022]
- Covid protection may be boosted by genes, study shows - Yahoo News Australia - October 13th, 2022 [October 13th, 2022]
- Genomics in Cancer Care Market is estimated to be US$ 72.61 billion by 2032 with a CAGR of 16.3% during the forecast period 2032 - By PMI -... - October 13th, 2022 [October 13th, 2022]
- Identification of hub genes and candidate herbal treatment in obesity through integrated bioinformatic analysis and reverse network pharmacology |... - October 13th, 2022 [October 13th, 2022]
- Our *Homo sapiens* ancestors shared the world with Neanderthals, Denisovans and other types of humans whose DNA lives on in our genes -... - October 8th, 2022 [October 8th, 2022]
- Blue Eyed People Have a Single Ancestor | History of Yesterday - History of Yesterday - October 6th, 2022 [October 6th, 2022]
- Heart infection could be cause of death of Polish, US hero - ABC News - October 6th, 2022 [October 6th, 2022]
- 23andMe Announces Trials-in-Progress Poster Presentation on 23ME-00610, An Investigational Antibody Targeting CD200R1, at The Society for... - October 6th, 2022 [October 6th, 2022]
- The Genetic Drivers Of Longevity In Mice, Humans And Worms - Science 2.0 - October 6th, 2022 [October 6th, 2022]
- ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma | Communications Biology - Nature.com - October 6th, 2022 [October 6th, 2022]
- 'Neanderthal Man' Nobel Prize winner Svante Pbo revolutionized anthropology. Here is a look back at his groundbreaking 2014 memoir - Genetic Literacy... - October 6th, 2022 [October 6th, 2022]
- Understanding Human Genetic Variation - NCBI Bookshelf - September 14th, 2022 [September 14th, 2022]
- Genetics - National Institute of General Medical Sciences (NIGMS) - September 14th, 2022 [September 14th, 2022]
- People with ME invited to take part in major genetic study - The Independent - September 14th, 2022 [September 14th, 2022]
- Ketamine Promising for Rare Condition Linked to Autism - Medscape - September 14th, 2022 [September 14th, 2022]
- How a small, unassuming fish helps reveal gene adaptations - University of Wisconsin-Madison - September 14th, 2022 [September 14th, 2022]
- How Nutrigenomics Explores Links Between Nutrition And Genes - Health Digest - September 14th, 2022 [September 14th, 2022]