Search Our Scientific Publications & Authors

Am J Hum Genet 2022 May 12. Epub 2022 May 12.

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland.

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. Read More

Am J Hum Genet 2022 May 13. Epub 2022 May 13.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Open Targets, Wellcome Genome Campus, Hinxton CB10 1SD, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Puddicombe Way, Cambridge CB2 0AW, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge CB2 0QQ, UK; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK; Human Technopole, Palazzo Italia, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy. Electronic address:

Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0. Read More

Am J Hum Genet 2022 May 10. Epub 2022 May 10.

Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK. Electronic address:

The spleen plays a key role in iron homeostasis. It is the largest filter of the blood and performs iron reuptake from old or damaged erythrocytes. Despite this role, spleen iron concentration has not been measured in a large, population-based cohort. Read More

Am J Hum Genet 2022 May 6. Epub 2022 May 6.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA. Electronic address:

Glioma is a highly fatal cancer with prognostically significant molecular subtypes and few known risk factors. Multiple studies have implicated infections in glioma susceptibility, but evidence remains inconsistent. Genetic variants in the human leukocyte antigen (HLA) region modulate host response to infection and have been linked to glioma risk. Read More

Am J Hum Genet 2022 May;109(5):973

Department of Physiology and Pharmacology, Biomedicum, Karolinska Institutet, 171 77 Stockholm, Sweden; Institute of Sport Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania. Electronic address:

Am J Hum Genet 2022 May;109(5):967-972

Estonian Biocentre, Institute of Genomics, University of Tartu, Riia 23B, Tartu 51010, Estonia; Department of Human Genetics, KU Leuven, Leuven, Herestraat 3000, Belgium. Electronic address:

The common loss-of-function mutation R577X in the structural muscle protein ACTN3 emerged as a potential target of positive selection from early studies and has been the focus of insightful physiological work suggesting a significant impact on muscle metabolism. Adaptation to cold climates has been proposed as a key adaptive mechanism explaining its global allele frequency patterns. Here, we re-examine this hypothesis analyzing modern (n = 3,626) and ancient (n = 1,651) genomic data by using allele-frequency as well as haplotype homozygosity-based methods. Read More

Am J Hum Genet 2022 May;109(5):825-837

Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Transcriptome-wide association studies and colocalization analysis are popular computational approaches for integrating genetic-association data from molecular and complex traits. They show the unique ability to go beyond variant-level genetic-association evidence and implicate critical functional units, e.g. Read More

Am J Hum Genet 2022 Apr 29. Epub 2022 Apr 29.

Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA; Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address:

More knowledge is needed regarding germline predisposition to Ewing sarcoma to inform biological investigation and clinical practice. Here, we evaluated the enrichment of pathogenic germline variants in Ewing sarcoma relative to other pediatric sarcoma subtypes, as well as patterns of inheritance of these variants. We carried out European-focused and pan-ancestry case-control analyses to screen for enrichment of pathogenic germline variants in 141 established cancer predisposition genes in 1,147 individuals with pediatric sarcoma diagnoses (226 Ewing sarcoma, 438 osteosarcoma, 180 rhabdomyosarcoma, and 303 other sarcoma) relative to identically processed cancer-free control individuals. Read More

Am J Hum Genet 2022 Apr 27. Epub 2022 Apr 27.

Department of Biostatistics, University of Michigan, Ann Arbor, MI 48105, USA; Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA.

Genotype imputation is an integral tool in genome-wide association studies, in which it facilitates meta-analysis, increases power, and enables fine-mapping. With the increasing availability of whole-genome-sequence datasets, investigators have access to a multitude of reference-panel choices for genotype imputation. In principle, combining all sequenced whole genomes into a single large panel would provide the best imputation performance, but this is often cumbersome or impossible due to privacy restrictions. Read More

Am J Hum Genet 2022 Apr 26. Epub 2022 Apr 26.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

Current publicly available tools that allow rapid exploration of linkage disequilibrium (LD) between markers (e.g., HaploReg and LDlink) are based on whole-genome sequence (WGS) data from 2,504 individuals in the 1000 Genomes Project. Read More

Am J Hum Genet 2022 Apr 21. Epub 2022 Apr 21.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address:

Most disease-associated genetic variants are pleiotropic, affecting multiple genetically correlated traits. Their pleiotropic associations can be mechanistically informative: if many variants have similar patterns of association, they may act via similar pleiotropic mechanisms, forming a shared component of heritability. We developed pleiotropic decomposition regression (PDR) to identify shared components and their underlying genetic variants. Read More

Am J Hum Genet 2022 May 22;109(5):953-960. Epub 2022 Apr 22.

Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia.

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Read More

Am J Hum Genet 2022 May 22;109(5):838-856. Epub 2022 Apr 22.

Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China; Center for Precision Medicine, Sun Yat-sen University, Guangzhou 510080, China. Electronic address:

Isolating the causal genes from numerous genetic association signals in genome-wide association studies (GWASs) of complex phenotypes remains an open and challenging question. In the present study, we proposed a statistical approach, the effective-median-based Mendelian randomization (MR) framework, for inferring the causal genes of complex phenotypes with the GWAS summary statistics (named EMIC). The effective-median method solved the high false-positive issue in the existing MR methods due to either correlation among instrumental variables or noises in approximated linkage disequilibrium (LD). Read More

Am J Hum Genet 2022 May 21;109(5):767-782. Epub 2022 Apr 21.

MRC Biostatistics Unit, University of Cambridge, Cambridge, UK; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Electronic address:

Mendelian randomization and colocalization are two statistical approaches that can be applied to summarized data from genome-wide association studies (GWASs) to understand relationships between traits and diseases. However, despite similarities in scope, they are different in their objectives, implementation, and interpretation, in part because they were developed to serve different scientific communities. Mendelian randomization assesses whether genetic predictors of an exposure are associated with the outcome and interprets an association as evidence that the exposure has a causal effect on the outcome, whereas colocalization assesses whether two traits are affected by the same or distinct causal variants. Read More

Am J Hum Genet 2022 May 13;109(5):802-811. Epub 2022 Apr 13.

Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA. Electronic address:

Heritability is a fundamental concept in genetic studies, measuring the genetic contribution to complex traits and bringing insights about disease mechanisms. The advance of high-throughput technologies has provided many resources for heritability estimation. Linkage disequilibrium (LD) score regression (LDSC) estimates both heritability and confounding biases, such as cryptic relatedness and population stratification, among single-nucleotide polymorphisms (SNPs) by using only summary statistics released from genome-wide association studies. Read More

Am J Hum Genet 2022 May 12;109(5):812-824. Epub 2022 Apr 12.

Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA. Electronic address:

The application of genetic relationships among individuals, characterized by a genetic relationship matrix (GRM), has far-reaching effects in human genetics. However, the current standard to calculate the GRM treats linked markers as independent and does not explicitly model the underlying genealogical history of the study sample. Here, we propose a coalescent-informed framework, namely the expected GRM (eGRM), to infer the expected relatedness between pairs of individuals given an ancestral recombination graph (ARG) of the sample. Read More

Am J Hum Genet 2022 May 8;109(5):928-943. Epub 2022 Apr 8.

Institute for Pathology, Medical Center - University of Freiburg, Medical Faculty, University of Freiburg, 79002 Freiburg, Germany.

Organ fibrosis is a shared endpoint of many diseases, yet underlying mechanisms are not well understood. Several pathways governed by the primary cilium, a sensory antenna present on most vertebrate cells, have been linked with fibrosis. Ciliopathies usually start early in life and represent a considerable disease burden. Read More

Am J Hum Genet 2022 May 8;109(5):961-966. Epub 2022 Apr 8.

Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Cardiology, Brigham and Women's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Harvard University, Boston, MA 02138, USA.

The well-established manifestation of mitochondrial mutations in functional cardiac disease (e.g., mitochondrial cardiomyopathy) prompted the hypothesis that mitochondrial DNA (mtDNA) sequence and/or copy number (mtDNAcn) variation contribute to cardiac defects in congenital heart disease (CHD). Read More

Am J Hum Genet 2022 Apr;109(4):759-763

Am J Hum Genet 2022 Apr;109(4):601-617

The Genomic Unit, Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel; The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel.

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. Read More

Am J Hum Genet 2022 Apr;109(4):549-552

Struthers Parkinson's Center, Golden Valley, MN 55427, USA. Electronic address:

Am J Hum Genet 2022 May 6;109(5):909-927. Epub 2022 Apr 6.

Université Paris Cité, Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris 75015, France. Electronic address:

Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Read More

Am J Hum Genet 2022 May 5;109(5):857-870. Epub 2022 Apr 5.

Boston University and the National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA; Department of Preventive Medicine and Epidemiology, School of Medicine and Public Health, Boston University, Boston, MA 02118, USA.

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV] and its ratio to forced vital capacity [FEV/FVC]) in the UK Biobank. Read More

Am J Hum Genet 2022 May 30;109(5):944-952. Epub 2022 Mar 30.

Institute for Clinical Genetics, Bonn 53111, Germany.

Calcium (Ca) is a universal second messenger involved in synaptogenesis and cell survival; consequently, its regulation is important for neurons. ATPase plasma membrane Ca transporting 1 (ATP2B1) belongs to the family of ATP-driven calmodulin-dependent Ca pumps that participate in the regulation of intracellular free Ca. Here, we clinically describe a cohort of 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay. Read More

Am J Hum Genet 2022 May 29;109(5):900-908. Epub 2022 Mar 29.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.

Polygenic risk scores (PRSs) for a variety of diseases have recently been shown to have relative risks that depend on age, and genetic relative risks decrease with increasing age. A refined understanding of the age dependency of PRSs for a disease is important for personalized risk predictions and risk stratification. To further evaluate how the PRS relative risk for prostate cancer depends on age, we refined analyses for a validated PRS for prostate cancer by using 64,274 prostate cancer cases and 46,432 controls of diverse ancestry (82. Read More

Am J Hum Genet 2022 May 28;109(5):871-884. Epub 2022 Mar 28.

Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA; Department of Ecology, Evolution, and Organismal Biology, Brown University, Providence, RI 02912, USA; Data Science Initiative, Brown University, Providence, RI 02912, USA. Electronic address:

Since 2005, genome-wide association (GWA) datasets have been largely biased toward sampling European ancestry individuals, and recent studies have shown that GWA results estimated from self-identified European individuals are not transferable to non-European individuals because of various confounding challenges. Here, we demonstrate that enrichment analyses that aggregate SNP-level association statistics at multiple genomic scales-from genes to genomic regions and pathways-have been underutilized in the GWA era and can generate biologically interpretable hypotheses regarding the genetic basis of complex trait architecture. We illustrate examples of the robust associations generated by enrichment analyses while studying 25 continuous traits assayed in 566,786 individuals from seven diverse self-identified human ancestries in the UK Biobank and the Biobank Japan as well as 44,348 admixed individuals from the PAGE consortium including cohorts of African American, Hispanic and Latin American, Native Hawaiian, and American Indian/Alaska Native individuals. Read More

Am J Hum Genet 2022 May 24;109(5):783-801. Epub 2022 Mar 24.

Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Integrative analysis of genome-wide association studies (GWASs) and gene expression studies in the form of a transcriptome-wide association study (TWAS) has the potential to better elucidate the molecular mechanisms underlying disease etiology. Here we present a method, METRO, that can leverage gene expression data collected from multiple genetic ancestries to enhance TWASs. METRO incorporates expression prediction models constructed in different genetic ancestries through a likelihood-based inference framework, producing calibrated p values with substantially improved TWAS power. Read More

Am J Hum Genet 2022 May 23;109(5):885-899. Epub 2022 Mar 23.

Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Medical and Population Genetics Program, the Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Genome-wide association studies (GWASs) of Huntington disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals with a rater-estimated age at motor onset. To capitalize on the wealth of phenotypic data in several large HD natural history studies, we have performed algorithmic prediction by using common motor and cognitive measures to predict age at other disease landmarks as additional phenotypes for GWASs. Read More

Am J Hum Genet 2022 Apr 21;109(4):738-749. Epub 2022 Mar 21.

Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02215, USA.

A challenge in standard genetic studies is maintaining good power to detect associations, especially for low prevalent diseases and rare variants. The traditional methods are most powerful when evaluating the association between variants in balanced study designs. Without accounting for family correlation and unbalanced case-control ratio, these analyses could result in inflated type I error. Read More

Am J Hum Genet 2022 Apr 16;109(4):727-737. Epub 2022 Mar 16.

Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Inferring the structure of human populations from genetic variation data is a key task in population and medical genomic studies. Although a number of methods for population structure inference have been proposed, current methods are impractical to run on biobank-scale genomic datasets containing millions of individuals and genetic variants. We introduce SCOPE, a method for population structure inference that is orders of magnitude faster than existing methods while achieving comparable accuracy. Read More