Genetic associations with dementia‐related proteinopathy: Application of item response theory

• Published in: Alzheimer's & dementia 2024-04, Vol.20 (4), p.2906-2921
• Main Authors: Fardo, David W., Shade, Lincoln M. P., Wu, Xian, Karanth, Shama D., Hohman, Timothy J., Schneider, Julie A., Bennett, David A., Gauthreaux, Kathryn, Mock, Charles, Nelson, Peter T., Carrillo, Maria, Reiman, Eric M., Chen, Kewei, Saykin, Andrew J., Forghanian-Arani, Arvin, Borowski, Bret, Ward, Chad, Jones, David, Gunter, Jeff, Kantarci, Kejal, Senjem, Matthew, Vemuri, Prashanthi, Petersen, Ronald, Hsiao, John K., Potter, William, Ryan, Laurie, Silverberg, Nina, Conti, Cat, Sacrey, Diana Truran, Choe, Mark, Ashford, Miriam, Chen, Stephanie Rossi, Nudelman, Kelly, Foroud, Tatiana M., Shaw, Leslie M., Korecka, Magdalena, Figurski, Michal, Khachaturian, Zaven, Malone, Ian, Fox, Nick C., Beckett, Laurel, Weiner, Michael W., Landau, Susan, Jagust, William, Knaack, Alexander, DeCarli, Charles, Harvey, Danielle, Fletcher, Evan, Jin, Chengshi, Tosun‐Turgut, Duygu, Fockler, Juliet, Trojanowki, John Q., Das, Sandhitsu, Mathis, Chet, Toga, Arthur W., Zimmerman, Caileigh, Gessert, Devon, Shcrer, Elizabeth, Miller, Garrett, Coker, Godfrey, Jimenez, Gustavo, Salazar, Jennifer, Pizzola, Jeremy, Crawford, Karen, Donohue, Michael, Rafii, Michael, Adegoke, Olusegun, Aisen, Paul, Walter, Sarah, Moore, Shelley, Cabrera, Yuliana, Jahanshad, Neda, Thompson, Paul, Thomopoulos, Sophia I., Nir, Talia M., Montine, Tom, Okonkwo, Ozioma, Morris, John C., Taylor-Reinwald, Lisa, Perrin, Richard J., Fair, Brittany, Young, Amy, Hockens, Valerie, Buckley, Faith, Ida, Aileen, Almeda, Emily, Stephens, Kari A., Shibata, Dean K., Longstreth, Will, Che, Yen-Chi, Culhane, Jessica, Miller, Zack, Yasuda, Sarah, Mooney, Sean, Hubbard, Janene, Keller, Ben, Mcleod, Laura
• Format: Article
• Language: English
• Subjects: Alleles; Alzheimer's Coordinating Center; Alzheimer's disease; Alzheimer's Disease Neuroimaging Initiative; Alzheimer's disease neuropathologic changes (ADNC); Alzheimer's Disease Sequencing Project; ARHGEF28; Associations; Brain research; Candidates; Consortia; Credibility; Credit; Dementia; Disease; Genes; Genomes; Item response theory; Lewy; Neuropathology; Pathology; Public health; Religious Orders Study; RGNEF; Risk factors; Rush Memory and Aging Project (MAP); SDHAF1; TMEM68; Variants
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.13741

INTRODUCTION Although dementia‐related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia‐related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α‐synuclein, and TDP‐43. RESULTS Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP‐43‐, Aβ/Tau‐, and α‐synuclein‐related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP‐43 pathology; and GBA for α‐synuclein/Lewy bodies. Novel suggestive proteinopathy‐linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility. DISCUSSION A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies. Highlights Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.