☆ 4.7 Article

Manifestations of Alzheimer's disease genetic risk in the blood are evident in a multiomic analysis in healthy adults aged 18 to 90

SCIENTIFIC REPORTS (2022)

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SCIENTIFIC REPORTS
卷 12, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41598-022-09825-2

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Multidisciplinary Sciences

资金

  1. National Institutes of Health, National Institute on Aging [U01 AG046139, R01 AG061796, RF1 AG051504, R01-AG062634-01, U19 AG023122]
  2. National Institutes of Health, National Institute on Aging (NIH-NIA) [U01 AG032984, RC2 AG036528]
  3. National Institute on Aging (NIA) [U24 AG21886]
  4. National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania [U24-AG041689-01]
  5. NACC [U01 AG016976]
  6. NIA LOAD (Columbia University) [U24 AG026395, U24 AG026390, R01AG041797]
  7. Banner Sun Health Research Institute [P30 AG019610]
  8. Boston University [P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01 AG048927, R01AG33193, R01 AG009029]
  9. Columbia University [P50 AG008702, R37 AG015473, R01 AG037212, R01 AG028786]
  10. Duke University [P30 AG028377, AG05128]
  11. Emory University [AG025688]
  12. Group Health Research Institute [UO1 AG006781, UO1 HG004610, UO1 HG006375, U01 HG008657]
  13. Indiana University [P30 AG10133, R01 AG009956, RC2 AG036650]
  14. Johns Hopkins University [P50 AG005146, R01 AG020688]
  15. Massachusetts General Hospital [P50 AG005134]
  16. Mayo Clinic [P50 AG016574, R01 AG032990, KL2 RR024151]
  17. Mount Sinai School of Medicine [P50 AG005138, P01 AG002219]
  18. New York University [P30 AG08051, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137]
  19. North Carolina AT University [P20 MD000546, R01 AG28786-01A1]
  20. Northwestern University [P30 AG013854]
  21. Oregon Health & Science University [P30 AG008017, R01 AG026916]
  22. Rush University [RC2 AG036650, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG030146, R01 AG01101, R01 AG22018]
  23. TGen [R01 NS059873]
  24. University of Alabama at Birmingham [P50 AG016582]
  25. University of Arizona [R01 AG031581]
  26. University of California, Davis [P30 AG010129]
  27. University of California, Irvine [P50 AG016573]
  28. University of California, Los Angeles [P50 AG016570]
  29. University of California, San Diego [P50 AG005131]
  30. University of California, San Francisco [P50 AG023501, P01 AG019724]
  31. University of Kentucky [P30 AG028383, AG05144]
  32. University of Michigan [P50 AG008671]
  33. University of Pennsylvania [P30 AG010124]
  34. University of Pittsburgh [P50 AG005133, AG030653, AG041718, AG07562, AG02365]
  35. University of Southern California [P50 AG005142]
  36. University of Texas Southwestern [P30 AG012300]
  37. University of Miami [R01 AG027944, AG010491, AG027944, AG021547, AG019757]
  38. University of Washington [P50 AG005136, R01 AG042437]
  39. University of Wisconsin [P50 AG033514]
  40. Vanderbilt University [R01 AG019085]
  41. Washington University [P50 AG005681, P01 AG03991, P01 AG026276]
  42. NINDS [NS39764]
  43. NIMH [MH60451]
  44. Glaxo Smith Kline
  45. Alzheimer's Association [IIRG08-89720, IIRG-05-14147]
  46. US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program
  47. BrightFocus Foundation [A2111048]
  48. Wellcome Trust
  49. Howard Hughes Medical Institute
  50. Canadian Institute of Health Research
  51. Kronos Science
  52. NIA [AG041232]
  53. Banner Alzheimer's Foundation
  54. Johnnie B. Byrd Sr. Alzheimer's Institute
  55. Medical Research Council
  56. state of Arizona
  57. Medical Research Council, local NHS trusts and Newcastle University
  58. Higher Education Funding Council for England (HEFCE)
  59. Alzheimer's Research Trust (ART)
  60. BRACE
  61. North Bristol NHS Trust Research and Innovation Department
  62. DeNDRoN
  63. Stichting MS Research
  64. Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk
  65. International Parkinson Fonds
  66. Internationale Stiching Alzheimer Onderzoek
  67. National Institutes of Health [U01 AG024904]
  68. Department of Defense [W81XWH-12-2-0012]
  69. National Institute on Aging
  70. National Institute of Biomedical Imaging and Bioengineering

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This study investigated the phenotypic associations of late-onset Alzheimer's Disease (AD) genetic variants using a large-scale GWAS meta-analysis dataset. The results revealed significant associations between the genetic variants and blood markers, lipid metabolism, and immune response systems, suggesting their potential involvement in early-stage biological pathways to AD.
Genetics play an important role in late-onset Alzheimer's Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants and an AD-specific polygenic risk score (PGRS), adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed. We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. We did not observe associations between the PGRS and any analyte. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

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Correction Neurosciences

A consensus protocol for functional connectivity analysis in the rat brain (vol 26, pg 673, 2023)

Joanes Grandjean, Gabriel Desrosiers-Gregoire, Cynthia Anckaerts, Diego Angeles-Valdez, Fadi Ayad, David A. Barriere, Ines Blockx, Aleksandra Bortel, Margaret Broadwater, Beatriz M. Cardoso, Marina Celestine, Jorge E. Chavez-Negrete, Sangcheon Choi, Emma Christiaen, Perrin Clavijo, Luis Colon-Perez, Samuel Cramer, Tolomeo Daniele, Elaine Dempsey, Yujian Diao, Arno Doelemeyer, David Dopfel, Lenka Dvorakova, Claudia Falfan-Melgoza, Francisca F. Fernandes, Caitlin F. Fowler, Antonio Fuentes-Ibanez, Clement M. Garin, Eveline Gelderman, Carla E. M. Golden, Chao C. G. Guo, Marloes J. A. G. Henckens, Lauren A. Hennessy, Peter Herman, Nita Hofwijks, Corey Horien, Tudor M. Ionescu, Jolyon Jones, Johannes Kaesser, Eugene Kim, Henriette Lambers, Alberto Lazari, Sung-Ho Lee, Amanda Lillywhite, Yikang Liu, Yanyan Y. Liu, Alejandra Lopez-Castro, Xavier Lopez-Gil, Zilu Ma, Eilidh MacNicol, Dan Madularu, Francesca Mandino, Sabina Marciano, Matthew J. McAuslan, Patrick McCunn, Alison McIntosh, Xianzong Meng, Lisa Meyer-Baese, Stephan Missault, Federico Moro, Daphne M. P. Naessens, Laura J. Nava-Gomez, Hiroi Nonaka, Juan J. Ortiz, Jaakko Paasonen, Lore M. Peeters, Mickael Pereira, Pablo D. Perez, Marjory Pompilus, Malcolm Prior, Rustam Rakhmatullin, Henning M. Reimann, Jonathan Reinwald, Rodrigo Triana Del Rio, Alejandro Rivera-Olvera, Daniel Ruiz-Perez, Gabriele Russo, Tobias J. Rutten, Rie Ryoke, Markus Sack, Piergiorgio Salvan, Basavaraju G. Sanganahalli, Aileen Schroeter, Bhedita J. Seewoo, Erwan Selingue, Aline Seuwen, Bowen Shi, Nikoloz Sirmpilatze, Joanna A. B. Smith, Corrie Smith, Filip Sobczak, Petteri J. Stenroos, Milou Straathof, Sandra Strobelt, Akira Sumiyoshi, Kengo Takahashi, Maria E. Torres-Garcia, Raul Tudela, Monica van den Berg, Kajo van der Marel, Aran T. B. van Hout, Roberta Vertullo, Benjamin Vidal, Roel M. Vrooman, Victora X. Wang, Isabel Wank, David J. G. Watson, Ting Yin, Yongzhi Zhang, Stefan Zurbruegg, Sophie Achard, Sarael Alcauter, Dorothee P. Auer, Emmanuel L. Barbier, Juergen Baudewig, Christian F. Beckmann, Nicolau Beckmann, Guillaume J. P. C. Becq, Erwin L. A. Blezer, Radu Bolbos, Susann Boretius, Sandrine Bouvard, Eike Budinger, Joseph D. Buxbaum, Diana Cash, Victoria Chapman, Kai-Hsiang Chuang, Luisa Ciobanu, Bram F. Coolen, Jeffrey W. Dalley, Marc Dhenain, Rick M. Dijkhuizen, Oscar Esteban, Cornelius Faber, Marcelo Febo, Kirk W. Feindel, Gianluigi Forloni, Jeremie Fouquet, Eduardo A. Garza-Villarreal, Natalia Gass, Jeffrey C. Glennon, Alessandro Gozzi, Olli Groehn, Andrew Harkin, Arend Heerschap, Xavier Helluy, Kristina Herfert, Arnd Heuser, Judith R. Homberg, Danielle J. Houwing, Fahmeed Hyder, Giovanna Diletta Ielacqua, Ileana O. Jelescu, Heidi Johansen-Berg, Gen Kaneko, Ryuta Kawashima, Shella D. Keilholz, Georgios A. Keliris, Clare Kelly, Christian Kerskens, Jibran Y. Khokhar, Peter C. Kind, Jean-Baptiste Langlois, Jason P. Lerch, Monica A. Lopez-Hidalgo, Denise Manahan-Vaughan, Fabien Marchand, Rogier B. Mars, Gerardo Marsella, Edoardo Micotti, Emma Munoz-Moreno, Jamie Near, Thoralf Niendorf, Willem M. Otte, Patricia Pais-Roldan, Wen-Ju Pan, Roberto A. Prado-Alcala, Gina L. Quirarte, Jennifer Rodger, Tim Rosenow, Cassandra Sampaio-Baptista, Alexander Sartorius, Stephen J. Sawiak, Tom W. J. Scheenen, Noam Shemesh, Yen-Yu Ian Shih, Amir Shmuel, Guadalupe Soria, Ron Stoop, Garth J. Thompson, Sally M. Till, Nick Todd, Annemie van der Linden, Annette van der Toorn, Geralda A. F. van Tilborg, Christian Vanhove, Andor Veltien, Marleen Verhoye, Lydia Wachsmuth, Wolfgang Weber-Fahr, Patricia Wenk, Xin Yu, Valerio Zerbi, Nanyin Zhang, Baogui B. Zhang, Luc Zimmer, Gabriel A. Devenyi, M. Mallar Chakravarty, Andreas Hess

NATURE NEUROSCIENCE (2023)

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Article Multidisciplinary Sciences

Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Yu-Han Hsu, Greta Pintacuda, Ruize Liu, Eugeniu Nacu, Apri Kim, Kalliopi Tsafou, Natalie Petrossian, William Crotty, Jung Min Suh, Jackson Riseman, Jacqueline M. Martin, Julia C. Biagini, Daya Mena, Joshua K. T. Ching, Edyta Malolepsza, Taibo Li, Tarjinder Singh, Tian Ge, Shawn B. Egri, Benjamin Tanenbaum, Caroline R. Stanclift, Annie M. Apffel, Steven A. Carr, Monica Schenone, Jake Jaffe, Nadine Fornelos, Hailiang Huang, Kevin C. Eggan, Kasper Lage

Summary: Genetics have identified many schizophrenia risk genes and found common signals between schizophrenia and neurodevelopmental disorders. However, there is often a lack of functional interpretation of these genes in relevant brain cell types. In this study, the researchers investigated the protein network of six schizophrenia risk genes in induced cortical neurons, finding that it is enriched for common variant risk of schizophrenia and down-regulated in affected individuals. They also identified a sub-network centered on HCN1 that is enriched for common variant risk and contains proteins associated with rare protein-truncating mutations in schizophrenia and bipolar disorder. This study highlights the importance of brain cell-type-specific interactomes in interpreting genetic and transcriptomic data in schizophrenia and related disorders.

ISCIENCE (2023)

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Review Genetics & Heredity

Updated consensus guidelines on the management of Phelan-McDermid syndrome

Siddharth Srivastava, Mustafa Sahin, Joseph D. Buxbaum, Elizabeth Berry-Kravis, Latha Valluripalli Soorya, Audrey Thurm, Jonathan A. Bernstein, Afua Asante-Otoo, William E. E. Bennett Jr, Catalina Betancur, Tegwyn H. Brickhouse, Maria Rita Passos Bueno, Maya Chopra, Celanie K. Christensen, Jennifer L. Cully, Kira Dies, Kate Friedman, Brittany Gummere, J. Lloyd Holder Jr, Andres Jimenez-Gomez, Carolyn A. Kerins, Omar Khan, Teresa Kohlenberg, Ronald V. Lacro, Lori A. Levi, Tess Levy, Diane Linnehan, Loth Eva, Baharak Moshiree, Ann Neumeyer, Scott M. Paul, Katy Phelan, Antonio Persico, Robert Rapaport, Curtis Rogers, Jeffrey Saland, Swathi Sethuram, Janine Shapiro, Phillip I. Tarr, Kerry M. White, Jordan Wickstrom, Kent M. Williams, Dana Winrow, Brian Wishart, Alexander Kolevzon

Summary: Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. Updated clinical management guidelines have been established to reflect the latest knowledge in PMS and provide guidance for clinicians, researchers, and the general community. These guidelines were developed by a taskforce consisting of clinical experts in PMS and representatives from the parent community.

AMERICAN JOURNAL OF MEDICAL GENETICS PART A (2023)

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Article Genetics & Heredity

Prospective phenotyping of CHAMP1 disorder indicates that coding mutations may not act through haploinsufficiency

Tess Levy, Thariana Pichardo, Hailey Silver, Bonnie Lerman, Jessica Zweifach, Danielle Halpern, Paige M. Siper, Alexander Kolevzon, Joseph D. Buxbaum

Summary: The study investigates the differences between individuals with CHAMP1 gene mutations and those with deletions of the gene. It reveals that individuals with mutations have lower adaptive functioning and more severe clinical phenotype compared to those with deletions. The findings suggest that the pathogenesis of CHAMP1 disorder may differ between groups, which has implications for future therapies.

HUMAN GENETICS (2023)

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Editorial Material Clinical Neurology

What is the Parkinson Pandemic?

Roger Albin, Nikolas Grotewold

MOVEMENT DISORDERS (2023)

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Article Clinical Neurology

CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD

Lisa Pavinato, Andrea Delle Vedove, Diana Carli, Marta Ferrero, Silvia Carestiato, Jennifer L. Howe, Emanuele Agolini, Domenico A. Coviello, Ingrid van de Laar, Ping Yee Billie Au, Eleonora Di Gregorio, Alessandra Fabbiani, Susanna Croci, Maria Antonietta Mencarelli, Lucia P. Bruno, Alessandra Renieri, Danai Veltra, Christalena Sofocleous, Laurence Faivre, Benoit Mazel, Hana Safraou, Anne-Sophie Denomme-Pichon, Marjon A. van Slegtenhorst, Noor Giesbertz, Richard H. van Jaarsveld, Anna Childers, R. Curtis Rogers, Antonio Novelli, Silvia De Rubeis, Joseph D. Buxbaum, Stephen W. Scherer, Giovanni Battista Ferrero, Brunhilde Wirth, Alfredo Brusco

Summary: Pavinato et al. describe a novel autosomal dominant neurodevelopmental disorder associated with loss of CAPRIN1, a regulator of the transport/translation of neuronal mRNAs critical for synaptic plasticity. The disorder is characterized by language impairment/speech delay, intellectual disability, attention deficit hyperactivity disorder, and autism spectrum disorder. They demonstrate morphological and functional alterations associated with this disorder in human neuronal models.

BRAIN (2023)

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Article Genetics & Heredity

Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome

Michael S. Breen, Xuanjia Fan, Tess Levy, Rebecca M. Pollak, Brett Collins, Aya Osman, Anna S. Tocheva, Mustafa Sahin, Elizabeth Berry-Kravis, Latha Soorya, Audrey Thurm, Craig M. Powell, Jonathan A. Bernstein, Alexander Kolevzon, Joseph D. Buxbaum

Summary: By analyzing the peripheral blood transcriptome and serum metabolome of individuals with Phelan-McDermid syndrome (PMS), researchers discovered gene expression profiles closely related to 22q13.3 deletion size. Additionally, they found underexpressed genes in PMS participants with class II mutations, not linked to 22q13.3, which were associated with glycosphingolipid metabolism, NCAM1 interactions, and cytotoxic natural killer (NK) immune cell signatures. This study provides new insights into the molecular perturbations and potential therapeutic targets for PMS.

HUMAN GENETICS AND GENOMICS ADVANCES (2023)

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