Publications by authors named "John R B Perry"

152 Publications

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Nat Genet 2021 Sep 6;53(9):1311-1321. Epub 2021 Sep 6.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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http://dx.doi.org/10.1038/s41588-021-00923-xDOI Listing
September 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
August 2021

Genetic association study of childhood aggression across raters, instruments, and age.

Transl Psychiatry 2021 07 30;11(1):413. Epub 2021 Jul 30.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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http://dx.doi.org/10.1038/s41398-021-01480-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324785PMC
July 2021

Incident disease associations with mosaic chromosomal alterations on autosomes, X and Y chromosomes: insights from a phenome-wide association study in the UK Biobank.

Cell Biosci 2021 Jul 23;11(1):143. Epub 2021 Jul 23.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD, 20892, USA.

Background: Mosaic chromosomal alterations (mCAs) are large chromosomal gains, losses and copy-neutral losses of heterozygosity (LOH) in peripheral leukocytes. While many individuals with detectable mCAs have no notable adverse outcomes, mCA-associated gene dosage alterations as well as clonal expansion of mutated leukocyte clones could increase susceptibility to disease.

Results: We performed a phenome-wide association study (PheWAS) using existing data from 482,396 UK Biobank (UKBB) participants to investigate potential associations between mCAs and incident disease. Of the 1290 ICD codes we examined, our adjusted analysis identified a total of 50 incident disease outcomes associated with mCAs at PheWAS significance levels. We observed striking differences in the diseases associated with each type of alteration, with autosomal mCAs most associated with increased hematologic malignancies, incident infections and possibly cancer therapy-related conditions. Alterations of chromosome X were associated with increased lymphoid leukemia risk and, mCAs of chromosome Y were linked to potential reduced metabolic disease risk.

Conclusions: Our findings demonstrate that a wide range of diseases are potential sequelae of mCAs and highlight the critical importance of careful covariate adjustment in mCA disease association studies.
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http://dx.doi.org/10.1186/s13578-021-00651-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299574PMC
July 2021

GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health.

Nat Commun 2021 07 7;12(1):4178. Epub 2021 Jul 7.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes-CHEK2 and GIGYF1-reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04-11.81], p = 1.3 × 10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51-10.61], p = 1.8 × 10), 4 kg higher fat mass (p = 1.3 × 10), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10) and 4.5 kg lower handgrip strength (p = 4.7 × 10) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.
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http://dx.doi.org/10.1038/s41467-021-24504-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263756PMC
July 2021

Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour.

Nat Hum Behav 2021 Jul 1. Epub 2021 Jul 1.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.
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http://dx.doi.org/10.1038/s41562-021-01135-3DOI Listing
July 2021

Prepubertal Dietary and Plasma Phospholipid Fatty Acids Related to Puberty Timing: Longitudinal Cohort and Mendelian Randomization Analyses.

Nutrients 2021 May 30;13(6). Epub 2021 May 30.

MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus Box 285, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.

Dietary intakes of polyunsaturated, monounsaturated and saturated fatty acids (FAs) have been inconsistently associated with puberty timing. We examined longitudinal associations of prepubertal dietary and plasma phospholipid FAs with several puberty timing traits in boys and girls. In the Avon Longitudinal Study of Parents and Children, prepubertal fat intakes at 3-7.5 years and plasma phospholipid FAs at 7.5 years were measured. Timings of Tanner stage 2 genital or breast development and voice breaking or menarche from repeated reports at 8-17 years, and age at peak height velocity (PHV) from repeated height measurements at 5-20 years were estimated. In linear regression models with adjustment for maternal and infant characteristics, dietary substitution of polyunsaturated FAs for saturated FAs, and higher concentrations of dihomo-γ-linolenic acid (20:3n6) and palmitoleic acid (16:1n7) were associated with earlier timing of puberty traits in girls ( = 3872) but not boys ( = 3654). In Mendelian Randomization models, higher genetically predicted circulating dihomo-γ-linolenic acid was associated with earlier menarche in girls. Based on repeated dietary intake data, objectively measured FAs and genetic causal inference, these findings suggest that dietary and endogenous metabolic pathways that increase plasma dihomo-γ-linolenic acid, an intermediate metabolite of n-6 polyunsaturated FAs, may promote earlier puberty timing in girls.
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http://dx.doi.org/10.3390/nu13061868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228200PMC
May 2021

Genetic analyses identify widespread sex-differential participation bias.

Nat Genet 2021 05 22;53(5):663-671. Epub 2021 Apr 22.

Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.
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http://dx.doi.org/10.1038/s41588-021-00846-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611642PMC
May 2021

The CD94/NKG2A inhibitory receptor educates uterine NK cells to optimize pregnancy outcomes in humans and mice.

Immunity 2021 06 21;54(6):1231-1244.e4. Epub 2021 Apr 21.

Department of Obstetrics & Gynaecology, University of Cambridge, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK; University of Cambridge Centre for Trophoblast Research, Cambridge, UK. Electronic address:

The conserved CD94/NKG2A inhibitory receptor is expressed by nearly all human and ∼50% of mouse uterine natural killer (uNK) cells. Binding human HLA-E and mouse Qa-1, NKG2A drives NK cell education, a process of unknown physiological importance influenced by HLA-B alleles. Here, we show that NKG2A genetic ablation in dams mated with wild-type males caused suboptimal maternal vascular responses in pregnancy, accompanied by perturbed placental gene expression, reduced fetal weight, greater rates of smaller fetuses with asymmetric growth, and abnormal brain development. These are features of the human syndrome pre-eclampsia. In a genome-wide association study of 7,219 pre-eclampsia cases, we found a 7% greater relative risk associated with the maternal HLA-B allele that does not favor NKG2A education. These results show that the maternal HLA-B→HLA-E→NKG2A pathway contributes to healthy pregnancy and may have repercussions on offspring health, thus establishing the physiological relevance for NK cell education. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.immuni.2021.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211638PMC
June 2021

Immune cells lacking Y chromosome show dysregulation of autosomal gene expression.

Cell Mol Life Sci 2021 Apr 10;78(8):4019-4033. Epub 2021 Apr 10.

Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer's disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a "genetic wasteland", and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.
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http://dx.doi.org/10.1007/s00018-021-03822-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106578PMC
April 2021

A Polygenic Risk Score to Predict Future Adult Short Stature Among Children.

J Clin Endocrinol Metab 2021 Jun;106(7):1918-1928

Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Canada.

Context: Adult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared to mid-parental height.

Objective: To develop a polygenic risk score for adult height and evaluate its clinical utility.

Design: A polygenic risk score was constructed based on meta-analysis of genomewide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.

Subjects: Participants included 442 599 genotyped White British individuals in the UK Biobank and 941 genotyped child-parent trios of European ancestry in the ALSPAC cohort.

Interventions: None.

Main Outcome Measures: Standing height was measured using stadiometer; Standing height 2 SDs below the sex-specific population average was considered as short stature.

Results: Combined with sex, a polygenic risk score captured 71.1% of the total variance in adult height in the UK Biobank. In the ALSPAC cohort, the polygenic risk score was able to identify children who developed adulthood short stature with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of mid-parental height. Combining this polygenic risk score with mid-parental height or only one of the child's parent's height could improve the AUROC to at most 0.90. The polygenic risk score could also substitute mid-parental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood.

Conclusions: A polygenic risk score could be considered as an alternative or adjunct to mid-parental height to improve screening for children at risk of developing short stature in adulthood in European ancestry populations.
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http://dx.doi.org/10.1210/clinem/dgab215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266463PMC
June 2021

Response to Comment on "Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior".

Science 2021 03;371(6536)

Centre for Psychology and Evolution, School of Psychology, University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia.

Hamer argue that the variable "ever versus never had a same-sex partner" does not capture the complexity of human sexuality. We agree and said so in our paper. But Hamer neglect to mention that we also reported follow-up analyses showing substantial overlap of the genetic influences on our main variable and on more nuanced measures of sexual behavior, attraction, and identity.
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http://dx.doi.org/10.1126/science.aba5693DOI Listing
March 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Identification of a unique epigenetic profile in women with diminished ovarian reserve.

Fertil Steril 2021 03 4;115(3):732-741. Epub 2020 Dec 4.

Department of Obstetrics and Gynaecology, Department of Reproductive Medicine, Hospital Herlev, Copenhagen University, Copenhagen, Denmark.

Objective: To investigate whether epigenetic profiles of mural granulosa cells (MGC) and leukocytes from women with diminished ovarian reserve (DOR) differ from those of women with normal or high ovarian reserve.

Design: Prospectively collected material from a multicenter cohort of women undergoing fertility treatment.

Setting: Private and university-based facilities for clinical services and research.

Patient(s): One hundred and nineteen women of various ages and ovarian reserve status (antimüllerian hormone level) who provided blood samples and MGC.

Intervention(s): None.

Main Outcome Measure(s): Measures of epigenetic aging rates from whole-genome methylation array data: DNA methylation variability, age acceleration, DNA methylation telomere length estimator (DNAmTL), and accumulation of epimutations.

Result(s): Comparison of DOR or high ovarian reserve samples to controls (normal ovarian reserve) showed differential methylation variability between DOR and normal samples at 4,199 CpGs in MGC, and 447 between high and normal (false-discovery rate < 0.05). Variable sites in MGC from DOR were enriched in regions marked with the repressive histone modification H3K27me3, and also included genes involved in folliculogenesis, such as insulin growth factor 2 (IGF2) and antimüllerian hormone (AMH). Regardless of ovarian reserve, very few signals were detected in leukocytes, and no overlaps with those in MGC were found. Furthermore, we found a higher number of epimutations in MGC from women with DOR (Kruskal-Wallis test, difference in mean = 3,485).

Conclusion(s): The somatic cells of human ovarian follicles have a distinctive epigenetic profile in women with DOR. A high frequency of epimutations suggests premature aging. Ovarian reserve status was not reflected in the leukocyte epigenetic profile.
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http://dx.doi.org/10.1016/j.fertnstert.2020.09.009DOI Listing
March 2021

Genetic basis of falling risk susceptibility in the UK Biobank Study.

Commun Biol 2020 09 30;3(1):543. Epub 2020 Sep 30.

Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Both extrinsic and intrinsic factors predispose older people to fall. We performed a genome-wide association analysis to investigate how much of an individual's fall susceptibility can be attributed to genetics in 89,076 cases and 362,103 controls from the UK Biobank Study. The analysis revealed a small, but significant SNP-based heritability (2.7%) and identified three novel fall-associated loci (P ≤ 5 × 10). Polygenic risk scores in two independent settings showed patterns of polygenic inheritance. Risk of falling had positive genetic correlations with fractures, identifying for the first time a pathway independent of bone mineral density. There were also positive genetic correlations with insomnia, neuroticism, depressive symptoms, and different medications. Negative genetic correlations were identified with muscle strength, intelligence and subjective well-being. Brain, and in particular cerebellum tissue, showed the highest gene expression enrichment for fall-associated variants. Overall, despite the highly heterogenic nature underlying fall risk, a proportion of the susceptibility can be attributed to genetics.
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http://dx.doi.org/10.1038/s42003-020-01256-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527955PMC
September 2020

The NEMP family supports metazoan fertility and nuclear envelope stiffness.

Sci Adv 2020 Aug 28;6(35):eabb4591. Epub 2020 Aug 28.

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada.

Human genome-wide association studies have linked single-nucleotide polymorphisms (SNPs) in () with early menopause; however, it is unclear whether NEMP1 has any role in fertility. We show that whole-animal loss of NEMP1 homologs in , , zebrafish, and mice leads to sterility or early loss of fertility. Loss of Nemp leads to nuclear shaping defects, most prominently in the germ line. Biochemical, biophysical, and genetic studies reveal that NEMP proteins support the mechanical stiffness of the germline nuclear envelope via formation of a NEMP-EMERIN complex. These data indicate that the germline nuclear envelope has specialized mechanical properties and that NEMP proteins play essential and conserved roles in fertility.
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http://dx.doi.org/10.1126/sciadv.abb4591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455189PMC
August 2020

Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan.

Nat Commun 2020 03 24;11(1):1536. Epub 2020 Mar 24.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus Box 285, Cambridge, CB2 0QQ, UK.

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes.
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http://dx.doi.org/10.1038/s41467-020-14451-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093467PMC
March 2020

Using human genetics to understand the disease impacts of testosterone in men and women.

Nat Med 2020 02 10;26(2):252-258. Epub 2020 Feb 10.

Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, Cambridge, UK.

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.
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http://dx.doi.org/10.1038/s41591-020-0751-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025895PMC
February 2020

Genetic predisposition to mosaic Y chromosome loss in blood.

Nature 2019 11 20;575(7784):652-657. Epub 2019 Nov 20.

Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
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http://dx.doi.org/10.1038/s41586-019-1765-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887549PMC
November 2019

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation.

Nat Commun 2019 10 17;10(1):4719. Epub 2019 Oct 17.

Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, 230-0045, Japan.

Mosaic loss of chromosome Y (mLOY) is frequently observed in the leukocytes of ageing men. However, the genetic architecture and biological mechanisms underlying mLOY are not fully understood. In a cohort of 95,380 Japanese men, we identify 50 independent genetic markers in 46 loci associated with mLOY at a genome-wide significant level, 35 of which are unreported. Lead markers overlap enhancer marks in hematopoietic stem cells (HSCs, P ≤ 1.0 × 10). mLOY genome-wide association study signals exhibit polygenic architecture and demonstrate strong heritability enrichment in regions surrounding genes specifically expressed in multipotent progenitor (MPP) cells and HSCs (P ≤ 3.5 × 10). ChIP-seq data demonstrate that binding sites of FLI1, a fate-determining factor promoting HSC differentiation into platelets rather than red blood cells (RBCs), show a strong heritability enrichment (P = 1.5 × 10). Consistent with these findings, platelet and RBC counts are positively and negatively associated with mLOY, respectively. Collectively, our observations improve our understanding of the mechanisms underlying mLOY.
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http://dx.doi.org/10.1038/s41467-019-12705-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797717PMC
October 2019

Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study.

Diabetes 2019 12 10;68(12):2315-2326. Epub 2019 Sep 10.

MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical Medicine, University of Cambridge, Cambridge, U.K.

Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to , , and ). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at , with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.
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http://dx.doi.org/10.2337/db18-0290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868468PMC
December 2019

Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior.

Science 2019 08;365(6456)

Centre for Psychology and Evolution, School of Psychology, University of Queensland, St. Lucia, Brisbane QLD 4072, Australia.

Twin and family studies have shown that same-sex sexual behavior is partly genetically influenced, but previous searches for specific genes involved have been underpowered. We performed a genome-wide association study (GWAS) on 477,522 individuals, revealing five loci significantly associated with same-sex sexual behavior. In aggregate, all tested genetic variants accounted for 8 to 25% of variation in same-sex sexual behavior, only partially overlapped between males and females, and do not allow meaningful prediction of an individual's sexual behavior. Comparing these GWAS results with those for the proportion of same-sex to total number of sexual partners among nonheterosexuals suggests that there is no single continuum from opposite-sex to same-sex sexual behavior. Overall, our findings provide insights into the genetics underlying same-sex sexual behavior and underscore the complexity of sexuality.
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http://dx.doi.org/10.1126/science.aat7693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082777PMC
August 2019

Author Correction: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability.

Nat Neurosci 2019 Jul;22(7):1196

Department of Youth and Family, Utrecht University, Utrecht, the Netherlands.

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.
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http://dx.doi.org/10.1038/s41593-019-0402-7DOI Listing
July 2019

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Nat Genet 2019 05 1;51(5):804-814. Epub 2019 May 1.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
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http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019
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