{"title":"Common protein-altering variant in GFAP is associated with white matter lesions in the older Japanese population.","authors":"Yoshihiko Furuta, Masato Akiyama, Naoki Hirabayashi, Takanori Honda, Mao Shibata, Tomoyuki Ohara, Jun Hata, Chikashi Terao, Yukihide Momozawa, Yasuko Tatewaki, Yasuyuki Taki, Shigeyuki Nakaji, Tetsuya Maeda, Kenjiro Ono, Masaru Mimura, Kenji Nakashima, Jun-Ichi Iga, Minoru Takebayashi, Toshiharu Ninomiya","doi":"10.1038/s41525-024-00431-x","DOIUrl":"10.1038/s41525-024-00431-x","url":null,"abstract":"<p><p>The genetic architecture of white matter lesions (WMLs) in Asian populations has not been well-characterized. Here, we performed a genome-wide association study (GWAS) to identify loci associated with the WML volume. Brain MRI and DNA samples were collected from 9479 participants in the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD). The GWAS confirmed three known WML-associated loci (SH3PXD2A, GFAP, and TRIM47). The lead variant of GFAP was a common missense variant (p.D295N) in East Asians. Meta-GWAS using the publicly available summary statistics of UK Biobank identified one previously unreported locus 6q23.2 (SLC2A12). Integration with expression quantitative trait locus data implied the newly identified locus affects SLC2A12 expression. The effect sizes of 20 lead variants at the WML-associated loci were moderately correlated between JPSC-AD and UK Biobank. These results indicate that the alteration in GFAP protein caused by the common missense variant in East Asians influences the WML volume.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"59"},"PeriodicalIF":4.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Denis M Nyaga, Peter Tsai, Clare Gebbie, Hui Hui Phua, Patrick Yap, Polona Le Quesne Stabej, Sophie Farrow, Jing Rong, Gergely Toldi, Eric Thorstensen, Zornitza Stark, Sebastian Lunke, Kimberley Gamet, Jodi Van Dyk, Mark Greenslade, Justin M O'Sullivan
{"title":"Benchmarking nanopore sequencing and rapid genomics feasibility: validation at a quaternary hospital in New Zealand.","authors":"Denis M Nyaga, Peter Tsai, Clare Gebbie, Hui Hui Phua, Patrick Yap, Polona Le Quesne Stabej, Sophie Farrow, Jing Rong, Gergely Toldi, Eric Thorstensen, Zornitza Stark, Sebastian Lunke, Kimberley Gamet, Jodi Van Dyk, Mark Greenslade, Justin M O'Sullivan","doi":"10.1038/s41525-024-00445-5","DOIUrl":"10.1038/s41525-024-00445-5","url":null,"abstract":"<p><p>Approximately 200 critically ill infants and children in New Zealand are in high-dependency care, many suspected of having genetic conditions, requiring scalable genomic testing. We adopted an acute care genomics protocol from an accredited laboratory and established a clinical pipeline using Oxford Nanopore Technologies PromethION 2 solo system and Fabric GEM™ software. Benchmarking of the pipeline was performed using Global Alliance for Genomics and Health benchmarking tools and Genome in a Bottle samples (HG002-HG007). Evaluation of single nucleotide variants resulted in a precision and recall of 0.997 and 0.992, respectively. Small indel identification approached a precision of 0.922 and recall of 0.838. Large genomic variations from Coriell Copy Number Variation Reference Panel 1 were reliably detected with ~2 M long reads. Finally, we present results obtained from fourteen trio samples, ten of which were processed in parallel with a clinically accredited short-read rapid genomic testing pipeline (Newborn Genomics Programme; NCT06081075; 2023-10-12).</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"57"},"PeriodicalIF":4.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Riccardo Sangermano, Priya Gupta, Cherrell Price, Jinu Han, Julien Navarro, Christel Condroyer, Emily M Place, Aline Antonio, Shizuo Mukai, Xavier Zanlonghi, José-Alain Sahel, Stephanie DiTroia, Emily O'Heir, Jacque L Duncan, Eric A Pierce, Christina Zeitz, Isabelle Audo, Rachel M Huckfeldt, Kinga M Bujakowska
{"title":"Coding and non-coding variants in the ciliopathy gene CFAP410 cause early-onset non-syndromic retinal degeneration.","authors":"Riccardo Sangermano, Priya Gupta, Cherrell Price, Jinu Han, Julien Navarro, Christel Condroyer, Emily M Place, Aline Antonio, Shizuo Mukai, Xavier Zanlonghi, José-Alain Sahel, Stephanie DiTroia, Emily O'Heir, Jacque L Duncan, Eric A Pierce, Christina Zeitz, Isabelle Audo, Rachel M Huckfeldt, Kinga M Bujakowska","doi":"10.1038/s41525-024-00439-3","DOIUrl":"10.1038/s41525-024-00439-3","url":null,"abstract":"<p><p>Inherited retinal degenerations are blinding genetic disorders characterized by high genetic and phenotypic heterogeneity. In this retrospective study, we describe sixteen families with early-onset non-syndromic retinal degenerations in which affected probands carried rare bi-allelic variants in CFAP410, a ciliary gene previously associated with recessive Jeune syndrome. We detected twelve variants, eight of which were novel, including c.373+91A>G, which led to aberrant splicing. To our knowledge this is the first likely pathogenic deep-intronic variant identified in this gene. Analysis of all reported and novel CFAP410 variants revealed no clear correlation between the severity of the CFAP410-associated phenotypes and the identified causal variants. This is supported by the fact that the frequently encountered missense variant p.(Arg73Pro), often found in syndromic cases, was also associated with non-syndromic retinal degeneration. This study expands the current knowledge of CFAP410-associated ciliopathy by enriching its mutational landscape and supports its association with non-syndromic retinal degeneration.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"58"},"PeriodicalIF":4.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Simo Li, Sanami Takada, Ghada M H Abdel-Salam, Mohamed S Abdel-Hamid, Maha S Zaki, Mahmoud Y Issa, Aida M S Salem, Eriko Koshimizu, Atsushi Fujita, Ryoko Fukai, Toshio Ohshima, Naomichi Matsumoto, Noriko Miyake
{"title":"Biallelic loss-of-function variants in GON4L cause microcephaly and brain structure abnormalities.","authors":"Simo Li, Sanami Takada, Ghada M H Abdel-Salam, Mohamed S Abdel-Hamid, Maha S Zaki, Mahmoud Y Issa, Aida M S Salem, Eriko Koshimizu, Atsushi Fujita, Ryoko Fukai, Toshio Ohshima, Naomichi Matsumoto, Noriko Miyake","doi":"10.1038/s41525-024-00437-5","DOIUrl":"10.1038/s41525-024-00437-5","url":null,"abstract":"<p><p>We identified two homozygous truncating variants in GON4L [NM_001282860.2:c.62_63del, p.(Gln21Argfs*12) and c.5517+1G>A] in two unrelated families who presented prenatal-onset growth impairment, microcephaly, characteristic face, situs inversus, and developmental delay. The frameshift variant is predicted to invoke nonsense-mediated mRNA decay of all five known GON4L isoforms resulting in the complete loss of GON4L function. The splice site variant located at a region specific to the longer isoforms; therefore, defects of long GON4L isoforms may explain the phenotypes observed in the three patients. Knockdown of Gon4l in rat PC12 cells suppressed neurite outgrowth in vitro. gon4lb knockdown and knockout zebrafish successfully recapitulated the patients' phenotypes including craniofacial abnormalities. We also observed situs inversus in gon4lb-knockout zebrafish embryo. To our knowledge, the relationship between craniofacial abnormalities or situs inversus and gon4lb has not been reported before. Thus, our data provide evidence that GON4L is involved in craniofacial and left-right patterning during development.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"55"},"PeriodicalIF":4.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kheireddin Mufti, Miguel Cordova, Erika N Scott, Jessica N Trueman, Jessica M Lovnicki, Catrina M Loucks, Shahrad R Rassekh, Colin J D Ross, Bruce C Carleton
{"title":"Genomic variations associated with risk and protection against vincristine-induced peripheral neuropathy in pediatric cancer patients.","authors":"Kheireddin Mufti, Miguel Cordova, Erika N Scott, Jessica N Trueman, Jessica M Lovnicki, Catrina M Loucks, Shahrad R Rassekh, Colin J D Ross, Bruce C Carleton","doi":"10.1038/s41525-024-00443-7","DOIUrl":"10.1038/s41525-024-00443-7","url":null,"abstract":"<p><p>Vincristine-induced peripheral neuropathy is a common and highly debilitating toxicity from vincristine treatment that affects quality of life and often requires dose reduction, potentially affecting survival. Although previous studies demonstrated genetic factors are associated with vincristine neuropathy risk, the clinical relevance of most identified variants is limited by small sample sizes and unclear clinical phenotypes. A genome-wide association study was conducted in 1100 cases and controls matched by vincristine dose and genetic ancestry, uncovering a statistically significant (p < 5.0 × 10<sup>-8</sup>) variant in MCM3AP gene that substantially increases the risk of neuropathy and 12 variants protective against neuropathy within/near SPDYA, METTL8, PDE4D, FBN2, ZFAND3, NFIB, PAPPA, LRRTM3, NRG3, VTI1A, ARHGAP5, and ACTN1. A follow-up pathway analysis reveals the involvement of four key pathways, including nerve structure and development, myelination, neuronal transmission, and cytoskeleton/microfibril function pathways. These findings present potential actionable genomic markers of vincristine neuropathy and offer opportunities for tailored interventions to improve vincristine safety in children with cancer. This study is registered with ClinicalTrials.gov under the title National Active Surveillance Network and Pharmacogenomics of Adverse Drug Reactions in Children (ID NCT00414115, registered on December 21, 2006).</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"56"},"PeriodicalIF":4.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guy Karlebach, Robin Steinhaus, Daniel Danis, Maeva Devoucoux, Olga Anczuków, Gloria Sheynkman, Dominik Seelow, Peter N Robinson
{"title":"Alternative splicing is coupled to gene expression in a subset of variably expressed genes.","authors":"Guy Karlebach, Robin Steinhaus, Daniel Danis, Maeva Devoucoux, Olga Anczuków, Gloria Sheynkman, Dominik Seelow, Peter N Robinson","doi":"10.1038/s41525-024-00432-w","DOIUrl":"10.1038/s41525-024-00432-w","url":null,"abstract":"<p><p>Numerous factors regulate alternative splicing of human genes at a co-transcriptional level. However, how alternative splicing depends on the regulation of gene expression is poorly understood. We leveraged data from the Genotype-Tissue Expression (GTEx) project to show a significant association of gene expression and splicing for 6874 (4.9%) of 141,043 exons in 1106 (13.3%) of 8314 genes with substantially variable expression in nine GTEx tissues. About half of these exons demonstrate higher inclusion with higher gene expression, and half demonstrate higher exclusion, with the observed direction of coupling being highly consistent across different tissues and in external datasets. The exons differ with respect to multiple characteristics and are enriched for hundreds of isoform-specific Gene Ontology annotations suggesting an important regulatory mechanism. Notably, splicing-expression coupling of exons with roles in JUN and MAP kinase signalling could play an important role during cell division.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"54"},"PeriodicalIF":4.7,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Trine O Eskesen, Kristian Almstrup, Laurits Elgaard, Tobias Arleth, Mathilde L Lassen, Andreas Creutzburg, Alice Herrlin Jensen, Niklas Breindahl, Felicia Dinesen, Malene Vang, Erik Sørensen, Anders Wallin Paulsen, Tatiana Nielsen, Lars S Rasmussen, Martin Sillesen, Jacob Steinmetz
{"title":"Severe traumatic injury is associated with profound changes in DNA methylation.","authors":"Trine O Eskesen, Kristian Almstrup, Laurits Elgaard, Tobias Arleth, Mathilde L Lassen, Andreas Creutzburg, Alice Herrlin Jensen, Niklas Breindahl, Felicia Dinesen, Malene Vang, Erik Sørensen, Anders Wallin Paulsen, Tatiana Nielsen, Lars S Rasmussen, Martin Sillesen, Jacob Steinmetz","doi":"10.1038/s41525-024-00438-4","DOIUrl":"10.1038/s41525-024-00438-4","url":null,"abstract":"<p><p>Whether DNA methylation changes follow human physical trauma is uncertain. We aimed to investigate if severe trauma was associated with DNA methylation changes. In a prospective, observational, clinical study, we included severely injured adults and adults undergoing elective surgery (controls). Blood was obtained from trauma patients (n = 60) immediately- and 30-45 days post-trauma, and from surgical patients (n = 57) pre-, post-, and 30-45 days post-surgery. Epigenome-wide DNA methylation profiling was performed and analyzed for significant differentially methylated CpGs and -regions (DMRs) within and between groups. Within the trauma group we identified 10,126 significant differentially methylated CpGs and 1169 DMRs. No significant differential methylation was found in the surgical group. In the trauma group, differentially methylated sites were enriched in genes and pathways involved in blood coagulation and inflammatory response. Severe trauma was associated with profound alterations in the DNA methylome of circulating leucocytes, and differential methylation was located in trauma-relevant genes.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"53"},"PeriodicalIF":4.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Junho Lee, Shin Ju Oh, Eunji Ha, Ga Young Shin, Hyo Jong Kim, Kwangwoo Kim, Chang Kyun Lee
{"title":"Gut microbial and human genetic signatures of inflammatory bowel disease increase risk of comorbid mental disorders.","authors":"Junho Lee, Shin Ju Oh, Eunji Ha, Ga Young Shin, Hyo Jong Kim, Kwangwoo Kim, Chang Kyun Lee","doi":"10.1038/s41525-024-00440-w","DOIUrl":"10.1038/s41525-024-00440-w","url":null,"abstract":"<p><p>The high prevalence of comorbid mental disorders (CMDs) in patients with inflammatory bowel disease (IBD) is well-documented. This study delves into the intricate CMD-IBD relationship through comprehensive analyses using human variants, gut microbiome, and anxiety/depression estimates from a cohort of 507 IBD patients and 75 controls. Notably, patients with IBD, especially those with CMD, exhibited lower diversity than controls. We identified 106 differentially abundant taxa (DATs) in IBD patients compared to controls and 21 DATs distinguishing CMD-affected from CMD-free IBD patients. Microbial IBD-risk scores, reflecting an individual's microbial burden for IBD, revealed a significant enrichment of IBD-risk signatures in CMD-affected patients compared to CMD-free patients. Additionally, there was an IBD-risk variant potentially regulating the abundance of an IBD/CMD-associated DAT, suggesting an interplay between IBD-risk variants and dysbiosis in CMD. Our investigation underscores the pivotal role of IBD-associated gut dysbiosis in predisposing IBD patients to CMD, partially through genetic variant-mediated mechanisms.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"52"},"PeriodicalIF":4.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jeny Bazalar-Montoya, Mario Cornejo-Olivas, Milagros M Duenas-Roque, Nelson Purizaca-Rosillo, Richard S Rodriguez, Karina Milla-Neyra, Carlos A De La Torre-Hernandez, Elison Sarapura-Castro, Carolina I Galarreta Aima, Gioconda Manassero-Morales, Giulliana Chávez-Pasco, Luis Celis-García, Jorge E La Serna-Infantes, Evgenii Chekalin, Erin Thorpe, Ryan J Taft
{"title":"Clinical genome sequencing in patients with suspected rare genetic disease in Peru.","authors":"Jeny Bazalar-Montoya, Mario Cornejo-Olivas, Milagros M Duenas-Roque, Nelson Purizaca-Rosillo, Richard S Rodriguez, Karina Milla-Neyra, Carlos A De La Torre-Hernandez, Elison Sarapura-Castro, Carolina I Galarreta Aima, Gioconda Manassero-Morales, Giulliana Chávez-Pasco, Luis Celis-García, Jorge E La Serna-Infantes, Evgenii Chekalin, Erin Thorpe, Ryan J Taft","doi":"10.1038/s41525-024-00434-8","DOIUrl":"10.1038/s41525-024-00434-8","url":null,"abstract":"<p><p>There is limited access to molecular genetic testing in most low- and middle-income countries. The iHope program provides clinical genome sequencing (cGS) to underserved individuals with signs or symptoms of rare genetic diseases and limited or no access to molecular genetic testing. Here we describe the performance and impact of cGS in 247 patients from three clinics in Peru. Although most patients had at least one genetic test prior to cGS (70.9%), the most frequent was karyotyping (53.4%). The diagnostic yield of cGS was 54.3%, with candidate variants reported in an additional 22.3% of patients. Clinical GS results impacted clinician diagnostic evaluation in 85.0% and genetic counseling in 72.1% of cases. Changes in management were reported in 71.3%, inclusive of referrals (64.7%), therapeutics (26.3%), laboratory or physiological testing (25.5%), imaging (19%), and palliative care (17.4%), suggesting that increased availability of genomic testing in Peru would enable improved patient management.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"51"},"PeriodicalIF":4.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11519459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Navid Nouri, Bailey Hannon Gussler, Amy Stockwell, Tom Truong, Gyeong Jin Kang, Kristen C Browder, Yann Malato, Abdoulaye Sene, Sherri Van Everen, Charles C Wykoff, David Brown, Arthur Fu, James D Palmer, Jose Ronaldo Lima de Carvalho, Ehsan Ullah, Ranya Al Rawi, Emily Y Chew, Wadih M Zein, Bin Guan, Mark I McCarthy, Jeffrey W Hofmann, Shawnta Y Chaney, Heinrich Jasper, Brian L Yaspan
{"title":"SLC16A8 is a causal contributor to age-related macular degeneration risk.","authors":"Navid Nouri, Bailey Hannon Gussler, Amy Stockwell, Tom Truong, Gyeong Jin Kang, Kristen C Browder, Yann Malato, Abdoulaye Sene, Sherri Van Everen, Charles C Wykoff, David Brown, Arthur Fu, James D Palmer, Jose Ronaldo Lima de Carvalho, Ehsan Ullah, Ranya Al Rawi, Emily Y Chew, Wadih M Zein, Bin Guan, Mark I McCarthy, Jeffrey W Hofmann, Shawnta Y Chaney, Heinrich Jasper, Brian L Yaspan","doi":"10.1038/s41525-024-00442-8","DOIUrl":"10.1038/s41525-024-00442-8","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD), a complex neurodegenerative disease, is a leading cause of visual impairment worldwide with a strong genetic component. Genetic studies have identified several loci, but few causal genes with functional characterization. Here we highlight multiple lines of evidence which show a causal role in AMD for SLC16A8, which encodes MCT3, a retinal pigment epithelium (RPE) specific lactate transporter. First, in an unbiased, genome-wide analysis of rare coding variants we show multiple SLC16A8 rare variants are associated with AMD risk, corroborating previous borderline significant reports from AMD rare variant studies. Second, we report a novel SLC16A8 mutation in a three-generation family with early onset macular degeneration. Finally, mis-expression in multiple model organisms shows functional and anatomic retinal consequences. This study highlights the important role for SLC16A8 and lactate regulation towards outer retina/RPE health and highlights a potential new therapeutic opportunity for the treatment of AMD.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"9 1","pages":"50"},"PeriodicalIF":4.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11519927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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