Exploring the noncoding genome with chromosomal structural rearrangements.

Highlighting the Distinguished Speakers Symposium on "The Future of Human Genetics and Genomics," this collection of articles is based on presentations at the ASHG 2023 Annual Meeting in Washington, DC, in celebration of all our field has accomplished in the past 75 years, since the founding of ASHG in 1948.

A comprehensive genome-wide cross-trait analysis of sexual factors and uterine leiomyoma.

Age at first sexual intercourse (AFS) and lifetime number of sexual partners (NSP) may influence the pathogenesis of uterine leiomyoma (UL) through their associations with hormonal concentrations and uterine infections. Leveraging summary statistics from large-scale genome-wide association studies conducted in European ancestry for each trait (NAFS = 214,547; NNSP = 370,711; NUL = 302,979), we observed a significant negative genomic correlation for UL with AFS (rg = -0.11, P = 7.83×10-4), but not with NSP (rg = 0.01, P = 0.62). Four specific genomic regions were identified as contributing significant local genetic correlations to AFS and UL, including one genomic region further identified for NSP and UL. Partitioning SNP-heritability with cell-type-specific annotations, a close clustering of UL with both AFS and NSP was identified in immune and blood-related components. Cross-trait meta-analysis revealed 15 loci shared between AFS/NSP and UL, including 7 novel SNPs. Univariable two-sample Mendelian randomization (MR) analysis suggested no evidence for a causal association between genetically predicted AFS/NSP and risk of UL, nor vice versa. Multivariable MR adjusting for age at menarche or/and age at natural menopause revealed a significant causal effect of genetically predicted higher AFS on a lower risk of UL. Such effect attenuated to null when age at first birth was further included. Utilizing participant-level data from the UK Biobank, one-sample MR based on genetic risk scores yielded consistent null findings among both pre-menopausal and post-menopausal females. From a genetic perspective, our study demonstrates an intrinsic link underlying sexual factors (AFS and NSP) and UL, highlighting shared biological mechanisms rather than direct causal effects. Future studies are needed to elucidate the specific mechanisms involved in the shared genetic influences and their potential impact on UL development.

Investigating the shared genetic architecture of uterine leiomyoma and breast cancer: A genome-wide cross-trait analysis.

Little is known regarding the shared genetic architecture or causality underlying the phenotypic association observed for uterine leiomyoma (UL) and breast cancer (BC). Leveraging summary statistics from the hitherto largest genome-wide association study (GWAS) conducted in each trait, we investigated the genetic overlap and causal associations of UL with BC overall, as well as with its subtypes defined by the status of estrogen receptor (ER). We observed a positive genetic correlation between UL and BC overall (rg = 0.09, p = 6.00 × 10-3), which was consistent in ER+ subtype (rg = 0.06, p = 0.01) but not in ER- subtype (rg = 0.06, p = 0.08). Partitioning the whole genome into 1,703 independent regions, local genetic correlation was identified at 22q13.1 for UL with BC overall and with ER+ subtype. Significant genetic correlation was further discovered in 9 out of 14 functional categories, with the highest estimates observed in coding, H3K9ac, and repressed regions. Cross-trait meta-analysis identified 9 novel loci shared between UL and BC. Mendelian randomization demonstrated a significantly increased risk of BC overall (OR = 1.09, 95% CI = 1.01-1.18) and ER+ subtype (OR = 1.09, 95% CI = 1.01-1.17) for genetic liability to UL. No reverse causality was found. Our comprehensive genome-wide cross-trait analysis demonstrates a shared genetic basis, pleiotropic loci, as well as a putative causal relationship between UL and BC, highlighting an intrinsic link underlying these two complex female diseases.

Genetic contribution of reproductive traits to risk of uterine leiomyomata: a large-scale, genome-wide, cross-trait analysis.

BACKGROUND: Although phenotypic associations between female reproductive characteristics and uterine leiomyomata have long been observed in epidemiologic investigations, the shared genetic architecture underlying these complex phenotypes remains unclear. OBJECTIVE: We aimed to investigate the shared genetic basis, pleiotropic effects, and potential causal relationships underlying reproductive traits (age at menarche, age at natural menopause, and age at first birth) and uterine leiomyomata. STUDY DESIGN: With the use of large-scale, genome-wide association studies conducted among women of European ancestry for age at menarche (n=329,345), age at natural menopause (n=201,323), age at first birth (n=418,758), and uterine leiomyomata (ncases/ncontrols=35,474/267,505), we performed a comprehensive, genome-wide, cross-trait analysis to examine systematically the common genetic influences between reproductive traits and uterine leiomyomata. RESULTS: Significant global genetic correlations were identified between uterine leiomyomata and age at menarche (rg, -0.17; P=3.65×10-10), age at natural menopause (rg, 0.23; P=3.26×10-07), and age at first birth (rg, -0.16; P=1.96×10-06). Thirteen genomic regions were further revealed as contributing significant local correlations (P<.05/2353) to age at natural menopause and uterine leiomyomata. A cross-trait meta-analysis identified 23 shared loci, 3 of which were novel. A transcriptome-wide association study found 15 shared genes that target tissues of the digestive, exo- or endocrine, nervous, and cardiovascular systems. Mendelian randomization suggested causal relationships between a genetically predicted older age at menarche (odds ratio, 0.88; 95% confidence interval, 0.85-0.92; P=1.50×10-10) or older age at first birth (odds ratio, 0.95; 95% confidence interval, 0.90-0.99; P=.02) and a reduced risk for uterine leiomyomata and between a genetically predicted older age at natural menopause and an increased risk for uterine leiomyomata (odds ratio, 1.08; 95% confidence interval, 1.06-1.09; P=2.30×10-27). No causal association in the reverse direction was found. CONCLUSION: Our work highlights that there are substantial shared genetic influences and putative causal links that underlie reproductive traits and uterine leiomyomata. The findings suggest that early identification of female reproductive risk factors may facilitate the initiation of strategies to modify potential uterine leiomyomata risk.

Concurrent Hearing and Genetic Screening of 180,469 Neonates with Follow-up in Beijing, China.

Concurrent hearing and genetic screening of newborns is expected to play important roles not only in early detection and diagnosis of congenital deafness, which triggers intervention, but also in predicting late-onset and progressive hearing loss and identifying individuals who are at risk of drug-induced HL. Concurrent hearing and genetic screening in the whole newborn population in Beijing was launched in January 2012. This study included 180,469 infants born in Beijing between April 2013 and March 2014, with last follow-up on February 24, 2018. Hearing screening was performed using transiently evoked otoacoustic emission (TEOAE) and automated auditory brainstem response (AABR). For genetic testing, dried blood spots were collected and nine variants in four genes, GJB2, SLC26A4, mtDNA 12S rRNA, and GJB3, were screened using a DNA microarray platform. Of the 180,469 infants, 1,915 (1.061%) were referred bilaterally or unilaterally for hearing screening; 8,136 (4.508%) were positive for genetic screening (heterozygote, homozygote, or compound heterozygote and mtDNA homoplasmy or heteroplasmy), among whom 7,896 (4.375%) passed hearing screening. Forty (0.022%) infants carried two variants in GJB2 or SLC26A4 (homozygote or compound heterozygote) and 10 of those infants passed newborn hearing screening. In total, 409 (0.227%) infants carried the mtDNA 12S rRNA variant (m.1555A>G or m.1494C>T), and 405 of them passed newborn hearing screening. In this cohort study, 25% of infants with pathogenic combinations of GJB2 or SLC26A4 variants and 99% of infants with an m.1555A>G or m.1494C>T variant passed routine newborn hearing screening, indicating that concurrent screening provides a more comprehensive approach for management of congenital deafness and prevention of ototoxicity.

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice.

Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicity-matched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.

Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth.

Epstein-Barr virus nuclear antigen 2 (EBNA2) regulation of transcription through the cell transcription factor RBPJ is essential for resting B-lymphocyte (RBL) conversion to immortal lymphoblast cell lines (LCLs). ChIP-seq of EBNA2 and RBPJ sites in LCL DNA found EBNA2 at 5,151 and RBPJ at 10,529 sites. EBNA2 sites were enriched for RBPJ (78%), early B-cell factor (EBF, 39%), RUNX (43%), ETS (39%), NFκB (22%), and PU.1 (22%) motifs. These motif associations were confirmed by LCL RBPJ ChIP-seq finding 72% RBPJ occupancy and Encyclopedia Of DNA Elements LCL ChIP-seq finding EBF, NFκB RELA, and PU.1 at 54%, 31%, and 17% of EBNA2 sites. EBNA2 and RBPJ were predominantly at intergene and intron sites and only 14% at promoter sites. K-means clustering of EBNA2 site transcription factors identified RELA-ETS, EBF-RUNX, EBF, ETS, RBPJ, and repressive RUNX clusters, which ranked from highest to lowest in H3K4me1 signals and nucleosome depletion, indicative of active chromatin. Surprisingly, although quantitatively less, the same genome sites in RBLs exhibited similar high-level H3K4me1 signals and nucleosome depletion. The EBV genome also had an LMP1 promoter EBF site, which proved critical for EBNA2 activation. LCL HiC data mapped intergenic EBNA2 sites to EBNA2 up-regulated genes. FISH and chromatin conformation capture linked EBNA2/RBPJ enhancers 428 kb 5' of MYC to MYC. These data indicate that EBNA2 evolved to target RBL H3K4me1 modified, nucleosome-depleted, nonpromoter sites to drive B-lymphocyte proliferation in primary human infection. The primed RBL program likely supports antigen-induced proliferation.

Genetics of Childhood Hearing Loss.

Compelling evidence indicates that some newborns harboring genetic variants associated with hearing loss might not be identified by current physiologic newborn hearing screening (NBHS) rendering current NBHS protocols suboptimal. Incorporating genomic sequencing into NBHS would improve clinical diagnosis and decrease time to early intervention efforts.