American journal of human genetics最新文献

{"title":"Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy.","authors":"Rebecca Buchert,Martin D Burkhalter,Chrisovalantou Huridou,Linda Sofan,Timo Roser,Kirsten Cremer,Javeria Raza Alvi,Stephanie Efthymiou,Tawfiq Froukh,Sughra Gulieva,Ulviyya Guliyeva,Moath Hamdallah,Muriel Holder-Espinasse,Rauan Kaiyrzhanov,Doreen Klingler,Mahmoud Koko,Lars Matthies,Joohyun Park,Marc Sturm,Ana Velic,Stephanie Spranger,Tipu Sultan,Hartmut Engels,Holger Lerche,Henry Houlden,Alistair T Pagnamenta,Ingo Borggraefe,Yvonne Weber,Penelope E Bonnen,Reza Maroofian,Olaf Riess,Jonasz J Weber,Melanie Philipp,Tobias B Haack","doi":"10.1016/j.ajhg.2024.12.019","DOIUrl":"https://doi.org/10.1016/j.ajhg.2024.12.019","url":null,"abstract":"Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy. These variants partly affected KICS2 stability, compromised KICSTOR complex formation, and demonstrated a deleterious impact on nutrient-dependent mTORC1 regulation of 4EBP1 and S6K. Phosphoproteome analyses extended these findings to show that KICS2 variants changed the mTORC1 proteome, affecting proteins that function in translation, splicing, and ciliogenesis. Depletion of Kics2 in zebrafish resulted in ciliary dysfunction consistent with a role of mTORC1 in cilia biology. These in vitro and in vivo functional studies confirmed the pathogenicity of identified KICS2 variants. Our genetic and experimental data provide evidence that variants in KICS2 are a factor involved in intellectual disability due to its dysfunction impacting mTORC1 regulation and cilia biology.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"28 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging diverse genomic data to guide equitable carrier screening: Insights from gnomAD v.4.1.0.","authors":"Matthew J Schmitz, Aryan Bashar, Vishal Soman, Esther A F Nkrumah, Hajer Al Mulla, Helia Darabi, John Wang, Paris Kiehl, Rahil Sethi, Jeffrey Dungan, Anthony R Gregg, Aleksandar Rajkovic, Svetlana A Yatsenko, Uma Chandran, Mahmoud Aarabi","doi":"10.1016/j.ajhg.2024.11.004","DOIUrl":"10.1016/j.ajhg.2024.11.004","url":null,"abstract":"<p><p>Analysis of exome data from the latest release of the Genome Aggregation Database (gnomAD v.4.1.0) revealed a significant carrier burden of pathogenic/likely pathogenic (P/LP) variants in genes associated with autosomal-recessive conditions across diverse ancestral populations. Carrier screening panels are routinely offered to reproductive partners to inform their risk of having an affected child. Current guidelines from the American College of Medical Genetics and Genomics (ACMG) recommend screening for genes with a carrier frequency of at least 1/200 and associated with moderate/severe conditions. Here, we systematically analyzed >700,000 gnomAD v.4.1.0 exomes spanning eight ancestries to estimate the carrier frequency of P/LP variants in 2,987 genes associated with autosomal-recessive conditions. After expert curation for clinical severity, we identified 286 genes meeting the criteria for carrier screening. The number of genes exceeding the 1/200 threshold varied across populations, with 40 in the South Asian ancestry and up to 119 in the Ashkenazi Jewish population. Simulations showed that pan-ethnic screening panels offer advantages for individuals of diverse or admixed ancestry, while ancestry-specific panels may be preferable for genetically homogeneous populations. This study leveraged the most comprehensive genomic dataset to date to provide an updated candidate gene list for equitable carrier screening across diverse populations. Our findings highlight the need for continued expansion of genomic resources to better understand rare disease risk and inform screening efforts in underrepresented groups.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"181-195"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype.","authors":"Thomas B Smith, Robert Kopajtich, Leigh A M Demain, Alessandro Rea, Huw B Thomas, Manuel Schiff, Christian Beetz, Shelagh Joss, Gerard S Conway, Anju Shukla, Mayuri Yeole, Periyasamy Radhakrishnan, Hatem Azzouz, Amel Ben Chehida, Monique Elmaleh-Bergès, Ruth I C Glasgow, Kyle Thompson, Monika Oláhová, Langping He, Emma M Jenkinson, Amir Jahic, Inna A Belyantseva, Melanie Barzik, Jill E Urquhart, James O'Sullivan, Simon G Williams, Sanjeev S Bhaskar, Samantha Carrera, Alexander J M Blakes, Siddharth Banka, Wyatt W Yue, Jamie M Ellingford, Henry Houlden, Kevin J Munro, Thomas B Friedman, Robert W Taylor, Holger Prokisch, Raymond T O'Keefe, William G Newman","doi":"10.1016/j.ajhg.2024.11.007","DOIUrl":"10.1016/j.ajhg.2024.11.007","url":null,"abstract":"<p><p>The mitochondrial ribosome (mitoribosome) synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA, and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders and frequently show combined oxidative phosphorylation deficiency. Here, we describe five unrelated individuals with bi-allelic variants in death-associated protein 3 (DAP3), a nuclear gene encoding mitoribosomal small subunit 29 (MRPS29), with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory-chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein amounts and, consequently, decreased levels of additional protein components of the mitoribosomal small subunit, as well as an associated combined deficiency of complexes I and IV. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression and partially rescued protein levels of MRPS7, MRPS9, and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants. Protein modeling suggested that DAP3 disease-associated missense variants can impact ADP binding, and in vitro assays demonstrated that DAP3 variants can consequently reduce both intrinsic and extrinsic apoptotic sensitivity, DAP3 thermal stability, and DAP3 GTPase activity. Our study presents genetic and functional evidence that bi-allelic variants in DAP3 result in a multisystem disorder of combined oxidative phosphorylation deficiency with pleiotropic presentations, consistent with mitochondrial dysfunction.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"59-74"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Bodmer and Charlesworth: Mendelian genetics and eugenics.","authors":"Adam Rutherford","doi":"10.1016/j.ajhg.2024.12.004","DOIUrl":"10.1016/j.ajhg.2024.12.004","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 1","pages":"198"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus.","authors":"Marcello Scala, Clarrisa A Bradley, Jennifer L Howe, Brett Trost, Nelson Bautista Salazar, Carole Shum, Marla Mendes, Miriam S Reuter, Evdokia Anagnostou, Jeffrey R MacDonald, Sangyoon Y Ko, Paul W Frankland, Jessica Charlebois, Mayada Elsabbagh, Leslie Granger, George Anadiotis, Verdiana Pullano, Alfredo Brusco, Roberto Keller, Sarah Parisotto, Helio F Pedro, Laina Lusk, Pamela Pojomovsky McDonnell, Ingo Helbig, Sureni V Mullegama, Emilie D Douine, Rosario Ivetth Corona, Bianca E Russell, Stanley F Nelson, Claudio Graziano, Maria Schwab, Laurie Simone, Federico Zara, Stephen W Scherer","doi":"10.1016/j.ajhg.2024.11.003","DOIUrl":"10.1016/j.ajhg.2024.11.003","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ∼1 Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS. While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been comprehensively examined, in part because there is no apparent functional murine ortholog. Through clinical testing, here, we identified 8 males and 2 females with ASD from 8 unrelated families carrying rare, predicted damaging or loss-of-function variants in DDX53. Additionally, we identified a family consisting of a male proband and his affected mother with high-functioning autism, both harboring a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 26 additional individuals with ASD harboring 19 mostly maternally inherited, rare, damaging DDX53 variations, including two variants detected in families from the original clinical analysis. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mice, may also influence the design and interpretation of murine modeling of ASD.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"154-167"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TEMR: Trans-ethnic mendelian randomization method using large-scale GWAS summary datasets.","authors":"Lei Hou, Sijia Wu, Zhongshang Yuan, Fuzhong Xue, Hongkai Li","doi":"10.1016/j.ajhg.2024.11.006","DOIUrl":"10.1016/j.ajhg.2024.11.006","url":null,"abstract":"<p><p>Available large-scale genome-wide association study (GWAS) summary datasets predominantly stem from European populations, while sample sizes for other ethnicities, notably Central/South Asian, East Asian, African, Hispanic, etc., remain comparatively limited, resulting in low precision of causal effect estimations within these ethnicities when using Mendelian randomization (MR). In this paper, we propose a trans-ethnic MR method, TEMR, to improve the statistical power and estimation precision of MR in a target population that is underrepresented, using trans-ethnic large-scale GWAS summary datasets. TEMR incorporates trans-ethnic genetic correlation coefficients through a conditional likelihood-based inference framework, producing calibrated p values with substantially improved MR power. In the simulation study, compared with other existing MR methods, TEMR exhibited superior precision and statistical power in causal effect estimation within the target populations. Finally, we applied TEMR to infer causal relationships between concentrations of 16 blood biomarkers and the risk of developing five diseases (hypertension, ischemic stroke, type 2 diabetes, schizophrenia, and major depression disorder) in East Asian, African, and Hispanic/Latino populations, leveraging biobank-scale GWAS summary data obtained from individuals of European descent. We found that the causal biomarkers were mostly validated by previous MR methods, and we also discovered 17 causal relationships that were not identified using previously published MR methods.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"28-43"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Demographic history and genetic variation of the Armenian population.","authors":"Anahit Hovhannisyan, Pierpaolo Maisano Delser, Anna Hakobyan, Eppie R Jones, Joshua G Schraiber, Mariya Antonosyan, Ashot Margaryan, Zhe Xue, Sungwon Jeon, Jong Bhak, Peter Hrechdakian, Hovhannes Sahakyan, Lehti Saag, Zaruhi Khachatryan, Levon Yepiskoposyan, Andrea Manica","doi":"10.1016/j.ajhg.2024.10.022","DOIUrl":"10.1016/j.ajhg.2024.10.022","url":null,"abstract":"<p><p>We introduce a sizable (n = 34) whole-genome dataset on Armenians, a population inhabiting the region in West Asia known as the Armenian highlands. Equipped with this genetic data, we conducted a whole-genome study of Armenians and deciphered their fine-scale population structure and complex demographic history. We demonstrated that the Armenian populations from western, central, and eastern parts of the highlands are relatively homogeneous. The Sasun, a population in the south that had been argued to have received a major genetic contribution from Assyrians, was instead shown to have derived its slightly divergent genetic profile from a bottleneck that occurred in the recent past. We also investigated the debated question on the genetic origin of Armenians and failed to find any significant support for historical suggestions by Herodotus of their Balkan-related ancestry. We checked the degree of continuity of modern Armenians with ancient inhabitants of the eastern Armenian highlands and detected a genetic input into the region from a source linked to Neolithic Levantine Farmers at some point after the Early Bronze Age. Additionally, we cataloged an abundance of new mutations unique to the population, including a missense mutation predicted to cause familial Mediterranean fever, an autoinflammatory disorder highly prevalent in Armenians. Thus, we highlight the importance of further genetic and medical studies of this population.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"11-27"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromosome X-wide common variant association study in autism spectrum disorder.","authors":"Marla Mendes, Desmond Zeya Chen, Worrawat Engchuan, Thiago Peixoto Leal, Bhooma Thiruvahindrapuram, Brett Trost, Jennifer L Howe, Giovanna Pellecchia, Thomas Nalpathamkalam, Roumiana Alexandrova, Nelson Bautista Salazar, Ethan A McKee, Natalia Rivera-Alfaro, Meng-Chuan Lai, Sara Bandres-Ciga, Delnaz Roshandel, Clarrisa A Bradley, Evdokia Anagnostou, Lei Sun, Stephen W Scherer","doi":"10.1016/j.ajhg.2024.11.008","DOIUrl":"10.1016/j.ajhg.2024.11.008","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes in ASD pathogenesis, such as MECP2, DDX3X, and DMD. The \"female protective effect\" in ASD suggests that females may require a higher genetic burden to manifest symptoms similar to those in males, yet the mechanisms remain unclear. Despite technological advances in genomics, the complexity of the biological nature of sex chromosomes leaves them underrepresented in genome-wide studies. Here, we conducted an X-chromosome-wide association study (XWAS) using whole-genome sequencing data from 6,873 individuals with ASD (82% males) across Autism Speaks MSSNG, Simons Simplex Collection (SSC), and Simons Powering Autism Research (SPARK), alongside 8,981 population controls (43% males). We analyzed 418,652 X chromosome variants, identifying 59 associated with ASD (p values 7.9 × 10^-6 to 1.51 × 10^-5), surpassing Bonferroni-corrected thresholds. Key findings include significant regions on Xp22.2 (lead SNP rs12687599, p = 3.57 × 10^-7) harboring ASB9/ASB11 and another encompassing DDX53 and the PTCHD1-AS long non-coding RNA (lead SNP rs5926125, p = 9.47 × 10^-6). When mapping genes within 10 kb of the 59 most significantly associated SNPs, 91 genes were found, 17 of which yielded association with ASD (GRPR, AP1S2, DDX53, HDAC8, PCDH19, PTCHD1, PCDH11X, PTCHD1-AS, DMD, SYAP1, CNKSR2, GLRA2, OFD1, CDKL5, GPRASP2, NXF5, and SH3KBP1). FGF13 emerged as an X-linked ASD candidate gene, highlighted by sex-specific differences in minor allele frequencies. These results reveal significant insights into X chromosome biology in ASD, confirming and nominating genes and pathways for further investigation.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"135-153"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-cancer analysis reveals age-associated genetic alterations in protein domains.","authors":"Haozhe Zou, Si Li, Jiyu Guo, Luan Wen, Chongwen Lv, Feng Leng, Zefeng Chen, Mengqian Zeng, Juan Xu, Yongsheng Li, Xia Li","doi":"10.1016/j.ajhg.2024.11.011","DOIUrl":"10.1016/j.ajhg.2024.11.011","url":null,"abstract":"<p><p>Cancer incidence and mortality differ among individuals of different ages, but the functional consequences of genetic alterations remain largely unknown. We systematically characterized genetic alterations within protein domains stratified by affected individual's age and showed that the mutational effects on domains varied with age. We further identified potential age-associated driver genes with hotspots across 33 cancers. The candidate drivers involved numerous cancer-related genes that participate in various oncogenic pathways and play central roles in human protein-protein interaction (PPI) networks. We found widespread age biases in protein domains and identified the associations between hotspots and age. Age-stratified PPI networks perturbed by hotspots were constructed to illustrate the function of mutations enriched in domains. We found that hotspots in young adults were associated with premature senescence. In summary, we provided a catalog of age-associated hotspots and their perturbed networks, which may facilitate precision diagnostics and treatments for cancer.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"44-58"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation-based predictors of metabolic traits in Scottish and Singaporean cohorts.","authors":"Hannah M Smith, Hong Kiat Ng, Joanna E Moodie, Danni A Gadd, Daniel L McCartney, Elena Bernabeu, Archie Campbell, Paul Redmond, Adele Taylor, Danielle Page, Janie Corley, Sarah E Harris, Darwin Tay, Ian J Deary, Kathryn L Evans, Matthew R Robinson, John C Chambers, Marie Loh, Simon R Cox, Riccardo E Marioni, Robert F Hillary","doi":"10.1016/j.ajhg.2024.11.012","DOIUrl":"10.1016/j.ajhg.2024.11.012","url":null,"abstract":"<p><p>Exploring the molecular correlates of metabolic health measures may identify their shared and unique biological processes and pathways. Molecular proxies of these traits may also provide a more objective approach to their measurement. Here, DNA methylation (DNAm) data were used in epigenome-wide association studies (EWASs) and for training epigenetic scores (EpiScores) of six metabolic traits: body mass index (BMI), body fat percentage, waist-hip ratio, and blood-based measures of glucose, high-density lipoprotein cholesterol, and total cholesterol in >17,000 volunteers from the Generation Scotland (GS) cohort. We observed a maximum of 12,033 significant findings (p < 3.6 × 10^-8) for BMI in a marginal linear regression EWAS. By contrast, a joint and conditional Bayesian penalized regression approach yielded 27 high-confidence associations with BMI. EpiScores trained in GS performed well in both Scottish and Singaporean test cohorts (Lothian Birth Cohort 1936 [LBC1936] and Health for Life in Singapore [HELIOS]). The EpiScores for BMI and total cholesterol performed best in HELIOS, explaining 20.8% and 7.1% of the variance in the measured traits, respectively. The corresponding results in LBC1936 were 14.4% and 3.2%, respectively. Differences were observed in HELIOS for body fat, where the EpiScore explained ∼9% of the variance in Chinese and Malay -subgroups but ∼3% in the Indian subgroup. The EpiScores also correlated with cognitive function in LBC1936 (standardized β_range: 0.08-0.12, false discovery rate p [p_FDR] < 0.05). Accounting for the correlation structure across the methylome can vastly affect the number of lead findings in EWASs. The EpiScores of metabolic traits are broadly applicable across populations and can reflect differences in cognition.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"106-115"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}