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Human Reproduction (Oxford, England) Jan 2024Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? (Meta-Analysis)
Meta-Analysis
STUDY QUESTION
Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins?
SUMMARY ANSWER
We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3.
WHAT IS KNOWN ALREADY
The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures.
STUDY DESIGN, SIZE, DURATION
We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls).
PARTICIPANTS/MATERIALS, SETTING, METHODS
Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation.
MAIN RESULTS AND THE ROLE OF CHANCE
This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle.
LARGE SCALE DATA
The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/).
LIMITATIONS, REASONS FOR CAUTION
Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility.
WIDER IMPLICATIONS OF THE FINDINGS
About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility.
STUDY FUNDING/COMPETING INTEREST(S)
Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Skłodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests.
TRIAL REGISTRATION NUMBER
N/A.
Topics: Animals; Female; Humans; Pregnancy; Carrier Proteins; Fertility; Genome-Wide Association Study; Hormones; Proteins; Twinning, Dizygotic; United States; Zebrafish
PubMed: 38052102
DOI: 10.1093/humrep/dead247 -
Tobacco Prevention & Cessation 2023Nicotine-containing products (NCPs) such as electronic nicotine delivery systems (ENDS) are increasingly common throughout the landscape of youth use of...
INTRODUCTION
Nicotine-containing products (NCPs) such as electronic nicotine delivery systems (ENDS) are increasingly common throughout the landscape of youth use of nicotine-containing products (NCP), and have overtaken traditional cigarette smoking modalities. This study seeks to examine the genetic and environmental influences on liability for susceptibility and initiation of ENDS and other NCPs among US children.
METHODS
Data were drawn from 886 monozygotic (MZ) and dizygotic (DZ) twin pairs aged 9-10 years in the Adolescent Brain & Cognitive Development (ABCD) study at the baseline during 2016-2018. Heritability (h) measured the proportion of the total phenotypic variation attributable to genes. Variance component models were utilized to analyze influences from the common environment (c) and unique environmental factors (e), taking into account correlations within twin pairs.
RESULTS
The national sample included 50% females, 69.5% of non-Hispanic Whites, 12.8% of non-Hispanic Blacks, and 11.6% of Hispanics, with a mean age of 121.5 months. The twin sets were 60% DZ and 40% MZ. Heritability was low for NCP susceptibility (h=0) and moderate for NCP initiation (h=39%, p=0.02). The variance associated with NCP susceptibility was primarily influenced by environmental factors, especially one's unique factors (c=37%, p<0.0001 vs e=63%, p<0.0001). In contrast, the variance associated with NCP initiation was split across common and unique environmental factors (c=32%, p=0.02 vs e=29%, p=0.02).
CONCLUSIONS
In the era with ENDS use surging among youth, NCP initiation remains to be a heritable trait with joint influence from the environment. NCP susceptibility is largely influenced by environmental factors, especially unique environments. Continued assessment of gene × environment interaction can better inform future youth NCP interventions.
PubMed: 38026821
DOI: 10.18332/tpc/173556 -
Twin Research and Human Genetics : the... Nov 2023Female fertility is a complex trait with age-specific changes in spontaneous dizygotic (DZ) twinning and fertility. To elucidate factors regulating female fertility and...
Female fertility is a complex trait with age-specific changes in spontaneous dizygotic (DZ) twinning and fertility. To elucidate factors regulating female fertility and infertility, we conducted a genome-wide association study (GWAS) on mothers of spontaneous DZ twins (MoDZT) versus controls (3273 cases, 24,009 controls). This is a follow-up study to the Australia/New Zealand (ANZ) component of that previously reported (Mbarek et al., 2016), with a sample size almost twice that of the entire discovery sample meta-analysed in the previous article (and five times the ANZ contribution to that), resulting from newly available additional genotyping and representing a significant increase in power. We compare analyses with and without male controls and show unequivocally that it is better to include male controls who have been screened for recent family history, than to use only female controls. Results from the SNP based GWAS identified four genomewide significant signals, including one novel region, (Zinc Finger Protein, FOG Family Member 1), on chromosome 16. Previous signals near (Follicle Stimulating Hormone beta subunit) and (SMAD Family Member 3) were also replicated (Mbarek et al., 2016). We also ran the GWAS with a dominance model that identified a further locus on chr 5. These results have been contributed to the International Twinning Genetics Consortium for inclusion in the next GWAS meta-analysis (Mbarek et al., in press).
PubMed: 37994447
DOI: 10.1017/thg.2023.45 -
BMC Medicine Nov 2023Emerging research suggests that attention-deficit/hyperactivity disorder (ADHD) increases the risk for cardiovascular (CVDs) and metabolic disorders (i.e.,...
BACKGROUND
Emerging research suggests that attention-deficit/hyperactivity disorder (ADHD) increases the risk for cardiovascular (CVDs) and metabolic disorders (i.e., cardiometabolic disorders) in adulthood. Yet, available studies are scarce and have mainly been focused on individuals receiving clinical ADHD diagnoses. We aimed to investigate the prospective associations of ADHD symptoms in young and mid-adulthood with subsequent cardiometabolic disorders and the underlying mechanisms.
METHODS
We studied 10,394 twins from the Swedish Twin Registry (STR), born between 1958 and 1985 without previous medical history of cardiometabolic disorders. They provided self-assessment of ADHD symptoms (score range 0-36) via a validated, DSM-IV-based scale in a web-based questionnaire/telephone interview within the Study of Twin Adults: Genes and Environment (STAGE), in 2005-2006 (aged 19-47 years), and were followed until the end of 2018 (33-59 years) to identify incident clinical diagnoses/medication prescriptions for cardiometabolic disorders acquired from Swedish national registers. We used Cox regression models to investigate the associations between ADHD symptoms score and cardiometabolic outcomes, with and without adjustment for relevant covariates, and a co-twin control design to study familial confounding.
RESULTS
A one-unit increase in the level of ADHD symptoms was associated with a 2% increase in the rate of CVDs (hazard ratio [HR] = 1.02, 95% confidence interval 1.01-1.04) and a 3% increase in the rate of metabolic disorders (HR = 1.03, 1.02-1.05), after adjusting for birth year and sex. The associations were no longer significant after adjusting for educational attainment, lifestyle factors, and comorbid psychiatric disorders. The associations remained significant after adjusting for familial factors shared by dizygotic twin pairs but became nonsignificant after adjusting for factors shared by monozygotic twin pairs. However, the strength of the associations attenuated significantly in monozygotic twins compared to dizygotic twins for CVDs only, suggesting genetic confounding.
CONCLUSIONS
ADHD symptom score is associated with a higher risk for cardiometabolic disorders, which may be explained by lower educational attainment, adverse lifestyle factors, and psychiatric comorbidities. Moreover, the associations appear to be partly confounded by shared genetic factors, especially for CVDs. Further research is needed to investigate the identified associations at the level of individual cardiometabolic disorders and to follow-up participants until a more advanced older age.
Topics: Female; Humans; Adult; Attention Deficit Disorder with Hyperactivity; Twins; Longitudinal Studies; Metabolic Diseases; Cardiovascular Diseases
PubMed: 37993878
DOI: 10.1186/s12916-023-03174-1 -
Journal of Neurodevelopmental Disorders Nov 2023Autism spectrum disorder (ASD) is associated with a diverse range of etiological processes, including both genetic and non-genetic causes. For a plurality of individuals... (Review)
Review
Autism spectrum disorder (ASD) is associated with a diverse range of etiological processes, including both genetic and non-genetic causes. For a plurality of individuals with ASD, it is likely that the primary causes involve multiple common inherited variants that individually account for only small levels of variation in phenotypic outcomes. This genetic landscape creates a major challenge for detecting small but important pathogenic effects associated with ASD. To address similar challenges, separate fields of medicine have identified endophenotypes, or discrete, quantitative traits that reflect genetic likelihood for a particular clinical condition and leveraged the study of these traits to map polygenic mechanisms and advance more personalized therapeutic strategies for complex diseases. Endophenotypes represent a distinct class of biomarkers useful for understanding genetic contributions to psychiatric and developmental disorders because they are embedded within the causal chain between genotype and clinical phenotype, and they are more proximal to the action of the gene(s) than behavioral traits. Despite their demonstrated power for guiding new understanding of complex genetic structures of clinical conditions, few endophenotypes associated with ASD have been identified and integrated into family genetic studies. In this review, we argue that advancing knowledge of the complex pathogenic processes that contribute to ASD can be accelerated by refocusing attention toward identifying endophenotypic traits reflective of inherited mechanisms. This pivot requires renewed emphasis on study designs with measurement of familial co-variation including infant sibling studies, family trio and quad designs, and analysis of monozygotic and dizygotic twin concordance for select trait dimensions. We also emphasize that clarification of endophenotypic traits necessarily will involve integration of transdiagnostic approaches as candidate traits likely reflect liability for multiple clinical conditions and often are agnostic to diagnostic boundaries. Multiple candidate endophenotypes associated with ASD likelihood are described, and we propose a new focus on the analysis of "endophenotype trait domains" (ETDs), or traits measured across multiple levels (e.g., molecular, cellular, neural system, neuropsychological) along the causal pathway from genes to behavior. To inform our central argument for research efforts toward ETD discovery, we first provide a brief review of the concept of endophenotypes and their application to psychiatry. Next, we highlight key criteria for determining the value of candidate endophenotypes, including unique considerations for the study of ASD. Descriptions of different study designs for assessing endophenotypes in ASD research then are offered, including analysis of how select patterns of results may help prioritize candidate traits in future research. We also present multiple candidate ETDs that collectively cover a breadth of clinical phenomena associated with ASD, including social, language/communication, cognitive control, and sensorimotor processes. These ETDs are described because they represent promising targets for gene discovery related to clinical autistic traits, and they serve as models for analysis of separate candidate domains that may inform understanding of inherited etiological processes associated with ASD as well as overlapping neurodevelopmental disorders.
Topics: Infant; Humans; Autism Spectrum Disorder; Endophenotypes; Language; Neurodevelopmental Disorders; Genetic Association Studies
PubMed: 37993779
DOI: 10.1186/s11689-023-09511-y -
Obesity (Silver Spring, Md.) Dec 2023This study investigated 36-year BMI trajectories in twins whose BMI in young adulthood was below, within, or above their genetically predicted BMI, with a focus on twin...
OBJECTIVE
This study investigated 36-year BMI trajectories in twins whose BMI in young adulthood was below, within, or above their genetically predicted BMI, with a focus on twin pairs with large intrapair BMI differences (within-pair ΔBMI ≥ 3 kg/m ).
METHODS
Together, 3227 like-sexed twin pairs (34% monozygotic) were examined at age ~30 years in 1975 and followed up in 1981, 1990, and 2011. An individual's observed BMI in 1975 was considered within (±2.0), below (<-2.0), or above (>+2.0) genetically predicted BMI, measured by a polygenic risk score of 996,919 single nucleotide polymorphisms.
RESULTS
In monozygotic and dizygotic twin pairs with large intrapair BMI differences, the co-twin with a higher observed BMI in 1975 deviated above predicted BMI more frequently (~2/3) than the co-twin with a lower BMI deviated below prediction (~1/3). Individuals below, within, and above prediction in 1975 reached, respectively, normal weight, overweight, and obesity by 2011, with a mean BMI increase of 4.5 (95% CI: 4.3-4.8).
CONCLUSIONS
Categorizing BMI as below, within, or above polygenic risk score-predicted BMI helps identifying individuals who have been resistant or susceptible to weight gain. This may provide new insights into determinants and consequences of obesity.
Topics: Adult; Humans; Body Mass Index; Finland; Longitudinal Studies; Obesity; Twins, Dizygotic; Twins, Monozygotic; Male; Female
PubMed: 37987187
DOI: 10.1002/oby.23906 -
International Journal of Surgery Case... Dec 2023The association in the occurrence of hypertrophic pyloric stenosis (HPS) is 0.25 % to 0.44 % between monozygotic twins and 0.05 % to 0.10 % in dizygotic twins. A...
INTRODUCTION AND IMPORTANCE
The association in the occurrence of hypertrophic pyloric stenosis (HPS) is 0.25 % to 0.44 % between monozygotic twins and 0.05 % to 0.10 % in dizygotic twins. A combination of genetic and environmental factors may have contributed to the occurrence of HPS. In view of the few related cases reported recently, we present two dizygotic twins who were diagnosed with HPS.
CASE PRESENTATION
This report describes a rare case of congenital infantile hypertrophic pyloric stenosis in preterm dizygotic twins diagnosed early, in which the first case presented with severe clinical features and managed surgically while the second presented with moderate features and hence managed non-operatively with atropine for 14 days. At 6 months of age, both twins continued to tolerate feeds, demonstrated satisfactory weight gain and had achieved appropriate developmental milestones. The postoperative course was uneventful in the twin A.
CLINICAL DISCUSSION
Congenital HPS in premature twins remains an underdiagnosed pathology due to its clinical picture mimicking digestive intolerance to feeds. The mean age at diagnosis is about 38 days, and only 0.4 % of all children suffering from HPS show symptoms in the first 3 days of life. Symptom relief is achieved after a classic pyloromyotomy is performed by a more preferable laparoscopic technique or using the open surgical technique.
CONCLUSION
If one of the dizygotic twins has HPS, the other baby should be evaluated for the same diagnosis as early as possible, to ensure timely management. HPS with moderate clinical features can be treated with atropine for 14 days while severe HPS should be treated by pyloromyotomy.
PubMed: 37980774
DOI: 10.1016/j.ijscr.2023.109069 -
Animals : An Open Access Journal From... Oct 2023Prenatal diagnosis comprises a set of investigations, both instrumental and laboratory-based, which aim to monitor the health of the foetus during pregnancy, from the...
Prenatal diagnosis comprises a set of investigations, both instrumental and laboratory-based, which aim to monitor the health of the foetus during pregnancy, from the early stages of embryonic development to the moments preceding delivery. A growing interest is emerging for the preterm ultrasound morphological screening of embryos and foetuses, aimed at assessing the integrity and viability of the conceptus, as well as the early diagnosis of anomalies which can cause complications. This study is a retrospective study of the ultrasonographic findings of twins in the authors' clinical activity from 2016 to 2022. Only seven cases of monochorionic twins were recorded, out of the whole number of evaluations performed on 3120 foetuses, with a prevalence of 0.6% and 0.2% in feline and canine foetuses. All the twins had their own amniotic sac and umbilical cord but presented a single placenta and a single allantoic sac. Unfortunately, the three feline cases were not more recognizable at term. In the four canine cases, three were of opposite sex and then necessarily dizygotic. Twins may have an impact on the success of a pregnancy due to the risk of dystocia, as observed in some of the reported cases. Prenatal ultrasound allows early recognition of twins in dogs and cats.
PubMed: 37958064
DOI: 10.3390/ani13213309 -
Ginekologia Polska 2024Evaluation of relative fetal growth in the form of estimated fetal weight discordance (EFWd) is a necessary element of any ultrasound examination in twin pregnancies. It... (Review)
Review
Evaluation of relative fetal growth in the form of estimated fetal weight discordance (EFWd) is a necessary element of any ultrasound examination in twin pregnancies. It is one of the criteria for the diagnosis of selective fetal growth restriction (sFGR) according to the most established worldwide guidelines. Apart from the effectiveness of this parameter for the diagnosis of sFGR, it may also be used as an independent factor for risk stratification of neonatal and maternal complications. Furthermore, numerous studies have proven the greater prognostic value of EFWd in dichorionic pregnancies, which may result from differences in the pathogenesis of fetal growth abnormalities in mono- and dichorionic pregnancies. Because of the variability of this parameter throughout pregnancy, there is an ongoing discussion regarding replacing or individualizing it with percentile charts. An additional element, complementary to EFWd in assessing the risk of complications in twin pregnancies is the use of this measurement in combination with Doppler assessment, which increases its predictive value. The use of EFWd as one of the factors influencing care and decision-making in dichorionic twin pregnancies seems to be a simple and effective method, however, further research assessing the use and possible applications of this indicator is necessary.
Topics: Humans; Female; Pregnancy; Pregnancy, Twin; Fetal Weight; Ultrasonography, Prenatal; Fetal Growth Retardation; Twins, Dizygotic; Fetal Development
PubMed: 37934897
DOI: 10.5603/gpl.96822 -
Genes Oct 2023The goal of the study was to explore the spectrum of pathogenic variants in the RPGR gene in a group of male Polish patients with a retinitis pigmentosa (RP) phenotype....
The goal of the study was to explore the spectrum of pathogenic variants in the RPGR gene in a group of male Polish patients with a retinitis pigmentosa (RP) phenotype. A total of 45 male index patients, including twins, being members of 44 families, were screened for pathogenic variants in the RPGR gene via the direct sequencing of PCR-amplified genomic DNA and underwent a comprehensive ophthalmological examination in one center located in Poland. A total of two pathogenic and five likely pathogenic variants in eight patients (18%) were detected in the studied cohort. Of these, five variants were novel, and five disease-causing variants (71%) were identified within the ORF15 mutational hotspot of the RPGR gene. The median age of onset of the disease was 10 years (range 6-14 years), the median age during the examination was 30 years (range 20-47 years), and the median visual acuity was 0.4 (range 0.01-0.7). The majority of patients had middle constriction of the visual field and thinning of the central foveal thickness. Dizygotic twins bearing the same hemizygous mutation showed a different retinal phenotype in regard to the severity of the symptoms. This is the first RPGR mutation screening in Poland showing a prevalence of 18% of RPGR pathogenic mutations and likely pathogenic variants in the studied cohort of male patients with an RP phenotype.
Topics: Humans; Male; Child; Adolescent; Young Adult; Adult; Middle Aged; Poland; Eye Proteins; Pedigree; Phenotype; Retinitis Pigmentosa
PubMed: 37895299
DOI: 10.3390/genes14101950