Biology subjects

Howrigan, D.

Publications and source records attributed to Howrigan, D..

7 recordsLinked to original sources

bioRxiv2026

Analysis of Rare Coding Variation Identifies New Genetic Contributors to Schizophrenia

In this study, we present the largest rare coding variant association study of schizophrenia to date, with 87,959 schizophrenia cases and 150,587 controls. We identify 16 genes at exome-wide significance: SETD1A, ZMYM2, HERC1, RB1CC1, SCAF1, XPO7, SP4, FYN, PPP3CA, CUL1, HDAC9, JARID2, ATP9A, PTK2, STAG1, and SCN2A, and an additional 24 at a 5% false discovery rate. Cases carrying ultra-rare, damaging variants, primarily protein-truncating and deleterious missense mutations, show strong enrichment in constrained genes with consistent effects across ancestries. Half of the 40 identified genes overlap with those implicated in developmental delay, autism, or bipolar disorder, underscoring shared neurodevelopmental risk. All 40 genes identified are highly expressed in excitatory and inhibitory neurons, and their expression patterns span diverse developmental stages. Functionally, the identified genes implicate chromatin regulation, protein degradation, and synaptic function. Overall, our results advance understanding of the genetic architecture of schizophrenia, provide a foundation for modeling risk genes in cellular and animal systems, and offer a framework for future work toward biologically informed patient stratification.

genetics↗

bioRxiv2025

Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood

One of the strongest signatures of aging is an accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy. Here we investigate the mechanism underlying this phenomenon by calling mtDNA sequence, abundance, and heteroplasmic variation in human blood using whole genome sequences from [~]750,000 individuals. Our analyses reveal a simple, two-step mechanism: first, individual cells randomly accumulate low levels of "cryptic" mtDNA mutations; then, when a cell clone proliferates, the cryptic mtDNA variants are carried as passenger mutations and become detectable in whole blood. Four lines of evidence support this model: (1) the mutational spectrum of age-accumulating mtDNA variants is consistent with a well-established model of mtDNA replication errors, (2) these mutations are found primarily at low levels of heteroplasmy and do not show evidence of positive selection, (3) high mtDNA mutation burden tends to co-occur in samples harboring somatic driver mutations for clonal hematopoiesis (CH), and (4) nuclear GWAS reveals that germline variants predisposing to CH (such as those near TERT, TCL1A, and SMC4) also increase mtDNA mutation burden. We propose that the high copy number and high mutation rate of mtDNA make it a particularly sensitive blood-based marker of CH. Importantly, our work helps to mechanistically unify three prominent signatures of aging: common germline variants in TERT, clonal hematopoiesis, and observed mtDNA mutation accrual.

genetics↗

bioRxiv2024

Blended Genome Exome (BGE) as a Cost Efficient Alternative to Deep Whole Genomes or Arrays

Genomic scientists have long been promised cheaper DNA sequencing, but deep whole genomes are still costly, especially when considered for large cohorts in population-level studies. More affordable options include microarrays + imputation, whole exome sequencing (WES), or low-pass whole genome sequencing (WGS) + imputation. WES + array + imputation has recently been shown to yield 99% of association signals detected by WGS. However, a method free from ascertainment biases of arrays or the need for merging different data types that still benefits from deeper exome coverage to enhance novel coding variant detection does not exist. We developed a new, combined, "Blended Genome Exome" (BGE) in which a whole genome library is generated, an aliquot of that genome is amplified by PCR, the exome regions are selected and enriched, and the genome and exome libraries are combined back into a single tube for sequencing (33% exome, 67% genome). This creates a single CRAM with a low-coverage whole genome (2-3x) combined with a higher coverage exome (30-40x). This BGE can be used for imputing common variants throughout the genome as well as for calling rare coding variants. We tested this new method and observed >99% r2 concordance between imputed BGE data and existing 30x WGS data for exome and genome variants. BGE can serve as a useful and cost-efficient alternative sequencing product for genomic researchers, requiring ten-fold less sequencing compared to 30x WGS without the need for complicated harmonization of array and sequencing data.

genomics↗

bioRxiv2021

Human genetic analyses of organelles highlight the nucleus in age-related trait heritability

Most age-related human diseases are accompanied by a decline in cellular organelle integrity, including impaired lysosomal proteostasis and defective mitochondrial oxidative phosphorylation. An open question, however, is the degree to which inherited variation in or near genes encoding each organelle contributes to age-related disease pathogenesis. Here, we evaluate if genetic loci encoding organelle proteomes confer greater-than-expected age-related disease risk. As mitochondrial dysfunction is a "hallmark" of aging, we begin by assessing nuclear and mitochondrial DNA loci near genes encoding the mitochondrial proteome and surprisingly observe a lack of enrichment across 24 age-related traits. Within nine other organelles, we find no enrichment with one exception: the nucleus, where enrichment emanates from nuclear transcription factors. In agreement, we find that genes encoding several organelles tend to be "haplosufficient," while we observe strong purifying selection against heterozygous protein-truncating variants impacting the nucleus. Our work identifies common variation near transcription factors as having outsize influence on age-related trait risk, motivating future efforts to determine if and how this inherited variation then contributes to observed age-related organelle deterioration.

genomics↗

bioRxiv2018

Schizophrenia risk conferred by protein-coding de novo mutations

Protein-coding de novo mutations (DNMs) in the form of single nucleotide changes and short insertions/deletions are significant genetic risk factors for autism, intellectual disability, developmental delay, and epileptic encephalopathy. In contrast, the burden of DNMs has thus far only had a modest documented impact on schizophrenia (SCZ) risk. Here, we analyze whole-exome sequence from 1,695 SCZ affected parent-offspring trios from Taiwan along with DNMs from 1,077 published SCZ trios to better understand the contribution of coding DNMs to SCZ risk. Among 2,772 SCZ affected probands, the increased burden of DNMs is modest. Gene set analyses show that the modest increase in risk from DNMs in SCZ probands is concentrated in genes that are either highly brain expressed, under strong evolutionary constraint, and/or overlap with genes identified as DNM risk factors in other neurodevelopmental disorders. No single gene meets the criteria for genome-wide significance, but we identify 16 genes that are recurrently hit by a protein-truncating DNM, which is a 3.15-fold higher rate than mutation model expectation of 5.1 genes (permuted 95% CI=1-10 genes, permuted p=3e-5). Overall, DNMs explain only a small fraction of SCZ risk, and this risk is polygenic in nature suggesting that coding variation across many different genes will be a risk factor for SCZ in the population.

genetics↗

bioRxiv2017

Heterogeneous Contribution of Microdeletions in the Development of Common Generalized and Focal epilepsies

BackgroundMicrodeletions are known to confer risk to epilepsy, particularly at genomic rearrangement \"hotspot\" loci. However, deciphering their role outside hotspots and risk assessment by epilepsy sub-type has not been conducted.\n\nMethodsWe assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1,366 patients with Genetic Generalized Epilepsy (GGE) plus two sets of additional unpublished genome-wide microdeletions found in 281 Rolandic Epilepsy (RE) and 807 Adult Focal Epilepsy (AFE) patients, totaling 2,454 cases. These microdeletion sets were assessed in a combined analysis and in sub-type specific approaches against 6,746 ethnically matched controls.\n\nResultsWhen hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted-P= 2.00x10-7; OR = 1.89; 95%-CI: 1.51-2.35), where the implicated microdeletions overlapped with rarely deleted genes and those involved in neurodevelopmental processes. Sub-type specific analyses showed that hotspot deletions in the GGE subgroup contribute most of the signal (adjusted-P = 1.22x10-12; OR = 7.45; 95%-CI = 4.20-11.97). Outside hotspot loci, microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted-P = 4.78x10-3; OR = 2.30; 95%-CI = 1.42-3.70), whereas no additional signal was observed for RE and AFE. Still, gene content analysis was able to identify known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes affected in more than one epilepsy sub-type but not in controls.\n\nConclusionsOur results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor to negligible contribution in the etiology of RE and AFE.

genetics↗

bioRxiv2017

Evolutionary and functional data power search for obsessive-compulsive disorder genes

Obsessive-compulsive disorder (OCD) is a severe psychiatric disorder linked to abnormalities in the cortico-striatal circuit and in glutamate signaling. We sequenced coding and regulatory elements for 608 genes implicated in OCD from humans and two animal models (mouse and dog). Using a new method, PolyStrat, which prioritizes variants disrupting evolutionarily conserved, functional regions, we found four strongly associated genes when comparing 592 cases to 560 controls. These results were validated in a second, larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains, while CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants. The rare coding variant burden in NRXN1 achieves genomewide significance (p=6.37x10-11) when we include public data for 33,370 controls. Of 17 regulatory variants identified in CTTNBP2 and REEP3, we show that at least six alter transcription factor-DNA binding in human neuroblastoma cells. Our findings suggest synaptic adhesion as a key function in compulsive behaviors across three species, and demonstrate how combining targeted sequencing with functional annotations can identify potentially causative variants in both coding and noncoding regions, even when genomic data is limited.

genomics↗