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Background: Maternal pre-pregnancy body-mass index (ppBMI) and gestational weight gain (GWG) are associated with cardiometabolic risk (CMR) traits in the offspring. The extent to which maternal genetic variation accounts for these associations is unknown.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Biological age (BA), reflecting aging-related health decline beyond chronological age, varies among individuals. While previous research explored associations of maternal pregnancy-related body size with offspring health outcomes, its implications for BA in young adults remain unclear. Utilizing longitudinal data of 1,148 mother-offspring pairs from the Jerusalem Perinatal Study, we analyzed associations of maternal pre-pregnancy BMI and gestational weight gain (GWG) with offspring Klemera-Doubal method (KDM)-based BA at age 32, and potential familial life-course underlying mechanisms. Maternal pregnancy-related body size, adjusted for sociodemographic/lifestyle factors was associated with offspring BA (βmaternal pre-pregnancy BMI=0.183,95%CI:0.098,0.267;βGWG=0.093,95%CI:0.021,0.165). Association of GWG with BA was largely direct (90%,95%CI,44%,100%), while association with maternal pre-pregnancy BMI was partially mediated through adolescent BMI (36%,95%CI=18%,75%), with both associations eliminated after adjustment for offspring adult BMI. Associations persisted after adjusting for offspring polygenic risk score for BMI (βmaternal pre-pregnancy BMI=0.128;95%CI=0.023,0.234; βGWG=0.102;95%CI=0.006,0.198), and somewhat altered after adjustment for maternal cardiometabolic conditions (βmaternal pre-pregnancy BMI=0.144,95%CI=0.059, 0.230). Impact on GWG associations was negligible. Thus, perinatal obesogenic environment contributes to offspring BA beyond sociodemographic factors and maternal cardiometabolic history, yet intergenerational transmission of obesity seems to underlie these associations. Nonetheless, the period between adolescence and young adulthood could be targeted for weight-reducing interventions, ultimately promoting healthy aging., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Parent-of-origin effect plays an important role in mammal development and disorder. Case-control mother-child pair genotype data can be used to detect parent-of-origin effect and is often convenient to collect in practice. Most existing methods for assessing parent-of-origin effect do not incorporate any covariates, which may be required to control for confounding factors. We propose to model the parent-of-origin effect through a logistic regression model, with predictors including maternal and child genotypes, parental origins, and covariates. The parental origins may not be fully inferred from genotypes of a target genetic marker, so we propose to use genotypes of markers tightly linked to the target marker to increase inference efficiency. A robust statistical inference procedure is developed based on a modified profile log-likelihood in a retrospective way. A computationally feasible expectation-maximization algorithm is devised to estimate all unknown parameters involved in the modified profile log-likelihood. This algorithm differs from the conventional expectation-maximization algorithm in the sense that it is based on a modified instead of the original profile log-likelihood function. The convergence of the algorithm is established under some mild regularity conditions. This expectation-maximization algorithm also allows convenient handling of missing child genotypes. Large sample properties, including weak consistency, asymptotic normality, and asymptotic efficiency, are established for the proposed estimator under some mild regularity conditions. Finite sample properties are evaluated through extensive simulation studies and the application to a real dataset.

Background/objectives: The effects of early life exposures on offspring life-course health are well established. This study assessed whether adding early socio-demographic and perinatal variables to a model based on polygenic risk score (PRS) improves prediction of obesity risk., Methods: We used the Jerusalem Perinatal study (JPS) with data at birth and body mass index (BMI) and waist circumference (WC) measured at age 32. The PRS was constructed using over 2.1M common SNPs identified in genome-wide association study (GWAS) for BMI. Linear and logistic models were applied in a stepwise approach. We first examined the associations between genetic variables and obesity-related phenotypes (e.g., BMI and WC). Secondly, socio-demographic variables were added and finally perinatal exposures, such as maternal pre-pregnancy BMI (mppBMI) and gestational weight gain (GWG) were added to the model. Improvement in prediction of each step was assessed using measures of model discrimination (area under the curve, AUC), net reclassification improvement (NRI) and integrated discrimination improvement (IDI)., Results: One standard deviation (SD) change in PRS was associated with a significant increase in BMI (β = 1.40) and WC (β = 2.45). These associations were slightly attenuated (13.7-14.2%) with the addition of early life exposures to the model. Also, higher mppBMI was associated with increased offspring BMI (β = 0.39) and WC (β = 0.79) (p < 0.001). For obesity (BMI ≥ 30) prediction, the addition of early socio-demographic and perinatal exposures to the PRS model significantly increased AUC from 0.69 to 0.73. At an obesity risk threshold of 15%, the addition of early socio-demographic and perinatal exposures to the PRS model provided a significant improvement in reclassification of obesity (NRI, 0.147; 95% CI 0.068-0.225)., Conclusions: Inclusion of early life exposures, such as mppBMI and maternal smoking, to a model based on PRS improves obesity risk prediction in an Israeli population-sample., (© 2024. The Author(s).)

Competing Interests: The authors declare that they do not have any conflicts of interest.

Microbiota composition has been linked to physical activity, health measures, and biological age, but a shared profile has yet to be shown. The aim of this study was to examine the associations between microbiota composition and measures of function, such as a composite measure of physical capacity, and biological age in midlife, prior to onset of age-related diseases. Seventy healthy midlife individuals (age 44.58 ± 0.18) were examined cross-sectionally, and their gut-microbiota profile was characterized from stool samples using 16SrRNA gene sequencing. Biological age was measured using the Klemera-Doubal method and a composition of blood and physiological biomarkers. Physical capacity was calculated based on sex-standardized functional tests. We demonstrate that the women had significantly richer microbiota, p = 0.025; however, microbiota diversity was not linked with chronological age, biological age, or physical capacity for either women or men. Men had slightly greater β-diversity; however, β-diversity was positively associated with biological age and with physical capacity for women only (p = 0.01 and p = 0.04; respectively). For women, an increase in abundance of Roseburia faecis and Collinsella aerofaciens, as well as genus Ruminococcus and Dorea, was significantly associated with higher biological age and lower physical capacity; an increase in abundance of Akkermansia muciniphila and genera Bacteroides and Alistipes was associated with younger biological age and increased physical capacity. Differentially abundant taxa were also associated with non-communicable diseases. These findings suggest that microbiota composition is a potential mechanism linking physical capacity and health status; personalized probiotics may serve as a new means to support health-promoting interventions in midlife. Investigating additional factors underlying this link may facilitate the development of a more accurate method to estimate the rate of aging., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Accurate placenta pathology assessment is essential for managing maternal and newborn health, but the placenta's heterogeneity and temporal variability pose challenges for histology analysis. To address this issue, we developed the 'Histology Analysis Pipeline.PY' (HAPPY), a deep learning hierarchical method for quantifying the variability of cells and micro-anatomical tissue structures across placenta histology whole slide images. HAPPY differs from patch-based features or segmentation approaches by following an interpretable biological hierarchy, representing cells and cellular communities within tissues at a single-cell resolution across whole slide images. We present a set of quantitative metrics from healthy term placentas as a baseline for future assessments of placenta health and we show how these metrics deviate in placentas with clinically significant placental infarction. HAPPY's cell and tissue predictions closely replicate those from independent clinical experts and placental biology literature., (© 2024. The Author(s).)

Background: Chromosomal-microarray-analysis (CMA) may reveal susceptibility-loci (SL) of varied penetrance for autism-spectrum-disorder (ASD) and other neurodevelopmental conditions. Attitudes of women/parents to disclosure of SL during pregnancy are understudied., Methods: A multiple-choice questionnaire was distributed to postpartum women. Data were collected on women's interest to receive prenatal genetic information with various levels of penetrance., Results: Women's (n = 941) disclosure choices were dependent on the magnitude of risk: approximately 70% supported disclosure of either full or 40% penetrance, 53% supported disclosure at a 20% risk threshold, and 40% supported disclosure at 10% or less. Although most women supported, rejected or were indecisive about disclosure consistently across all risk levels, nearly one-quarter (24%) varied their responses based on penetrance, and this was associated with religiosity, education, parity and concern about fetal health (p-values <0.04). Among those who varied their choices, the risk threshold was lower among secular women (20%) than among ultraorthodox women (40%). In a multivariable analysis, ultraorthodox women were much less likely to vary their choices on ASD disclosure compared with secular women (aOR = 0.37, p < 0.001)., Conclusion: Women's attitudes toward disclosure are influenced by the level of risk and their individual characteristics. We therefore encourage engaging women/couples in disclosure decisions regarding uncertain and probabilistic results from prenatal genomic tests., (© 2024 John Wiley & Sons Ltd.)

Background and Aims: Early life exposures affect offspring health across the life-course. We aimed to examine whether prevalent perinatal exposures and obstetric complications are independently associated with offspring overweight in adolescence. We then assessed whether shared maternal-offspring pathways drive the association of perinatal exposures with offspring overweight., Methods: Using data from the Jerusalem Perinatal Study birth cohort, two perinatal scores were constructed: obstetric complications (OC) and prevalent perinatal exposures (PPE) scores. PPE score, generated by principal component analysis, included three primary components. Logistic regressions were used to assess associations of scores with offspring overweight, with and without adjustment for maternal life-course survival., Results: OC and PPE scores were independently associated with offspring overweight (OR OC  = 1.15, 95%CI:1.07,1.25; OR PPE1- SEP and lifestyle  = 0.85, 95%CI:0.79,0.91; OR PPE2- Maternal body size  = 1.20, 95%CI: 1.13,1.28; OR PPE3-Fetal growth  = 1.18, 95%CI:1.11,1.26). Maternal survival was associated with offspring overweight (OR = 1.38, 95%CI:1.08,1.76), yet introducing PPE score to the same model attenuated this association (OR = 1.16, 95%CI:0.90, 1.49). When OC score and maternal survival were included in the same model, their associations with offspring overweight remained unchanged., Conclusions: Mother-offspring shared factors, captured by maternal life-course survival, underlie the effect of prevalent perinatal exposures on offspring overweight. However, the effect of obstetric complications was independent, highlighting the contribution of additional pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Chromosomal microarray analysis (CMA) may detect variants of uncertain clinical significance (VUS) and susceptibility loci (SL) with incomplete penetrance for neurodevelopmental disorders. This qualitative study provides empirical data on women's experiences with receiving such findings in pregnancy and their decisions regarding continuation or termination of the pregnancy., Methods: Semi-structured interviews were conducted with women who received a VUS and/or SL from prenatal CMA in the last 2-4 years and were analyzed using Grounded Theory., Results: The vast majority of women recalled being stressed by the findings. All women sought further advice and information to be able to decide whether to continue or terminate their pregnancy. The three pregnancies that were terminated have in common a de novo SL with a 10%-20% penetrance. Similar reasoning (coping with uncertainty, the quest for a perfect child, and a chance for recurrence in future pregnancies) led different women to contradicting conclusions regarding their pregnancies. All women felt satisfied with their decisions., Conclusion: Although uncertain/probabilistic information commonly involves a psychological burden, it may also be perceived as valuable and actionable. Pre-test parental choice regarding the disclosure of such information could allow personalized utilization of advanced genomic tests in pregnancy., (© 2023 John Wiley & Sons Ltd.)

Measures of biological age (BA) integrate information across organ systems to quantify "biological aging," i.e., inter-individual differences in aging-related health decline. While longevity and lifespan aggregate in families, reflecting transmission of genes and environments across generations, little is known about intergenerational continuity of biological aging or the extent to which this continuity may be modified by environmental factors. Using data from the Jerusalem Perinatal Study (JPS), we tested if differences in offspring BA were related to mortality in their parents. We measured BA using biomarker data collected from 1473 offspring during clinical exams in 2007-2009, at age 32 ± 1.1. Parental mortality was obtained from population registry data for the years 2004-2016. We fitted parametric survival models to investigate the associations between offspring BA and parental all-cause and cause-specific mortality. We explored potential differences in these relationships by socioeconomic position (SEP) and offspring sex. Participants' BAs widely varied (SD = 6.95). Among those measured to be biologically older, parents had increased all-cause mortality (HR = 1.10, 95% CI: 1.08, 1.13), diabetes mortality (HR = 1.19, 95% CI: 1.08, 1.30), and cancer mortality (HR = 1.07, 95% CI: 1.02, 1.13). The association with all-cause mortality was stronger for families with low compared with high SEP (P interaction = 0.04) and for daughters as compared to sons (P interaction  < 0.001). Using a clinical-biomarker-based BA estimate, observable by young adulthood prior to the onset of aging-related diseases, we demonstrate intergenerational continuity of the aging process. Furthermore, variation in this familial aggregation according to household socioeconomic position (SEP) at offspring birth and between families of sons and daughters proposes that the environment alters individuals' aging trajectory set by their parents., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

Background: Pre- and perinatal events may be associated with an increased risk of inflammatory bowel disease [IBD]. We aimed to investigate the role of pre- and perinatal factors as potential risk factors for the development of IBD in a population with a follow-up of 50 years., Methods: We conducted a nested case-control study, reporting IBD incidence among individuals born in 1964-76, for whom pre- and perinatal exposures were reported as part of the Jerusalem Perinatal Study [JPS], by linking them to the database of the epidemiology group of the Israeli IBD Research Nucleus [epi-IIRN], including all IBD patients in Israel since 2005 and their matched controls., Results: We identified 2789 individuals within the epi-IIRN cohort who were also included in the JPS cohort [n = 90 079]: 746 IBD patients (405 with Crohn's disease [CD] and 341 with ulcerative colitis [UC]) and 2043 non-IBD controls. Those with a 'Non-western' family origin had decreased odds of developing CD and UC. High socioeconomic status was associated with CD but not UC. Low birth weight [≤2500 g] occurred less frequently in IBD cases compared to controls, especially in UC patients, showing a protective effect. Being the first born was associated with CD, and having older siblings lowered the odds of developing CD, decreasing 7% with each additional sibling. Smoking and breastfeeding data were available for a subset of individuals, but neither was associated with IBD development., Conclusion: This population-based study identifies several pre- and perinatal variables as predictors of IBD development. This information may be helpful to facilitate implementation of early diagnosis interventions and family follow-up protocols., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Advanced prenatal genomic technologies can identify risks for adult-onset (AO) conditions in the fetus, challenging the traditional purpose of prenatal testing. Professional guidelines commonly support disclosure of high-penetrance AO actionable conditions, yet attitudes of women/parents to these findings and factors affecting their attitudes are understudied., Methods: We explored 941 (77% response rate) postpartum women's attitudes towards receiving prenatal genetic information, and associations of sociodemographic, medical and psychological characteristics with their choices, focusing on AO conditions., Results: Women largely support the disclosure of actionable AO findings (58.4%), in line with professional guidelines. A third of the women also supported the disclosure of non-actionable AO conditions. Stronger religious observance (p < 0.001) and higher psychological distress (p = 0.024) were associated with decreased interest in receiving actionable AO conditions, whereas higher concern for fetal health yielded increased interest (p = 0.032). Attitudes towards disclosure were strongly associated with women's perceived benefit of such information for their own, partner's, and future child's health. Termination of pregnancy based on such information received very little support., Conclusion: In-light of the demonstrated understanding of nuanced genetic information and the observed diversity in attitudes, a culturally competent opt-in/out policy could be considered. If full-disclosure is practiced, support should be provided to those expressing higher levels of distress., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Purpose: To identify factors responsible for variation in health among married individuals, we investigated the independent associations of gaps in spousal age and education (or "heterogamy") with all-cause and cause-specific mortality as well as with survival of cancer patients., Methods: Using over four decades of follow-up data on 36,717 couples from Jerusalem (1964-2016), we compared heterogamous with homogamous couples., Results: Having a less educated spouse was associated with an increased risk for several outcomes in both genders, such as all-cause mortality in males (hazard ratio [HR] = 1.18, 95% confidence interval [CI]: 1.12, 1.25) and in females (HR = 1.11, CI: 1.01, 1.22). Having a more educated spouse was associated with decreased all-cause mortality in males (HR = 0.93, CI: 0.87, 0.99), but not in females. Having an older spouse was detrimental for health of both genders. For example, increased all-cause mortality was seen in men (HR = 1.22, CI: 1.10, 1.34) and in women (HR = 1.10, CI: 1.02, 1.19). A younger spouse was beneficial for some of the outcomes in males, such as decreased cancer-specific mortality (HR = 0.88, CI: 0.78, 0.99), but not in females., Conclusions: Spousal gaps in education and age may be independently associated with health outcomes. The observed relationships may be driven by combined amounts of marital strain as well as shared spousal resources (such as knowledge or income) depending on gender., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To systematically investigate the relationship between objective measures of physical capacity (e.g., cardio-respiratory fitness or daily step count) and biological age, measured in different ways., Data Source: PubMed; SCOPUS - Elsevier API; and Web of Science - ISI 1984-present, as well as contextual search engines used to identify additional relevant publications., Study Selection: Cross-sectional and longitudinal studies that assessed the association between objectively measured physical capacity and biological aging in adult individuals (age>18)., Results: Analysis of 28 studies demonstrated that physical capacity is positively associated with biological aging; the most dominant measures of physical capacity are muscular strength or gait speed. The majority of the studies estimated biological aging by a single methodology - either Leukocyte Telomere Length or DNA methylation levels., Conclusions: This systematic review of the objective physical capacity measures used to estimate aging finds that the current literature is limited insofar as it overlooks the potential contribution of many feasible markers. We recommend measuring physical capacity in the context of aging using a wide range of modifiable behavioral markers, beyond simple muscle strength or simple gait speed. Forming a feasible and diversified method for estimating physical capacity through which it will also be possible to estimate biological aging in wide population studies is essential for the development of interventions that may alleviate the burden of age-related disease., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Gait speed, a central marker of aging, has been linked to various health outcomes, such as cognitive and physical functions in middle-aged adults. Although long-term systemic low-grade inflammation is considered a mechanism underlying a variety of aging-related risk factors, the longitudinal associations between inflammation markers and gait speed are yet to be fully investigated., Objective: To explore the associations of CRP and fibrinogen levels, measured two decades ago, with gait speed among community dwelling adults, considering the contribution of cardio-metabolic factors and cognition., Methods: Study participants took part in two phases of the of the "Kibbutzim Family Study" (i.e., Phase II, 1999-2000 and Phase III, 2017-2019). Blood samples collected in Phase II (baseline) were used to determine level of inflammatory markers. Gait speed was assessed under single-task (ST) and dual-task (DT) conditions in Phase III. Demographic, anthropometric and clinical data were collected in both phases. Linear regression models were used to assess the adjusted associations of inflammation and gait speed., Results: A total of 373 individuals aged 34-99 (mean 64 ± 13 years) in Phase III were included in the study. Gait speed under ST was negatively associated with baseline levels of fibrinogen ( b per standard deviation (SD) = -0.053, p = 0.0007) and CRP ( b per SD = -0.043, p = 0.010), after adjusting for baseline and concurrent cardiometabolic risk factors. Accounting for executive functions, associations of fibrinogen with gait under ST were somewhat attenuated, yet associations remained statistically significant ( p < 0.05). Associations with CRP were attenuated to the null. In contrast, there were no associations between inflammation markers and gait under DT., Conclusion: Our findings demonstrate that in a sample including younger to older adults, higher systemic inflammatory activity was linked with gait 20 years later, beyond age and cardiometabolic health, and to a certain extent, beyond executive functions. Thus, systemic inflammation may serve as an early marker to identify individuals at risk for gait decline., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Heumann, Youssim, Kizony, Friedlander, Shochat, Weiss, Hochner and Agmon.)

Objective: The purpose of this study was to investigate whether obstetric and perinatal socio-behavioral characteristics at the time of pregnancy predict obesity phenotypes of adult offspring., Methods: The Jerusalem Perinatal Study was conducted among 17,003 deliveries during 1974 to 1976. Follow-up studies were conducted during 2007 to 2009 and 2017 to 2019 among 1,440 offspring undergoing examinations. Offspring were classified into four phenotypes according to obesity and metabolic status: metabolically healthy normal weight (MHNW, reference group), unhealthy normal weight, healthy obesity (MHO), and unhealthy obesity (MUO). Regression models were carried out to identify perinatal predictors for risk phenotypes at age 30 to 35 years, emphasizing the differentiation between socio-behavioral and obstetric features., Results: A total of 15.7% of participants were classified as MUO, and 5.4% were classified as MHO. Low socioeconomic status was associated with both obesity phenotypes (e.g., odds ratio [OR] MHO/MHNW = 2.98, p < 0.001). High socioeconomic status was associated with MUO (OR MUO/MHNW = 1.93, p = 0.002). Maternal low education was also associated with both obesity phenotypes (OR MUO/MHNW = 2.46, p < 0.001, OR MHO/MHNW = 2.45, p = 0.005). Participants with MUO were more likely to have a smoking father (OR MUO/MHNW = 1.48, p = 0.021)., Conclusions: Perinatal socio-behavioral characteristics are associated with adult obesity phenotypes. The findings point to possible mechanisms underlying the development of obesity in young adults and, thus, contribute toward identifying high-risk groups that would mostly benefit from obesity risk-reduction interventions., (© 2021 The Obesity Society.)

It is of great interest to identify parent-of-origin effects (POEs) since POEs play an important role in many human heritable disorders and human early life growth and development. POE is sometimes referred to as imprinting effect in the literature. Compared with the standard logistic regression analyses, retrospective likelihood-based statistical methods are more powerful in identifying POEs when data are collected from related individuals retrospectively. However, none of existing retrospective-based methods can appropriately incorporate covariates that should be adjusted for if they are confounding factors. In this paper, a novel semiparametric statistical method, M-HAP, is developed to detect POEs by fully exploring available information from multilocus genotypes of case-control mother-child pairs and covariates. Some large sample properties are established for M-HAP. Finite sample properties of M-HAP are illustrated by extensive simulation studies and real data applications to the Jerusalem Perinatal Study and the Danish National Birth Cohort study, which confirm the desired superiority of M-HAP over some existing methods. M-HAP has been implemented in the updated R package CCMO., (© 2021 Wiley Periodicals LLC.)

Aim: This study aims to examine whether early-life factors are associated with adult ovarian reserve, measured by anti-Müllerian hormone (AMH) levels., Methods: The work is based on the Jerusalem Perinatal Study (JPS), an extensive birth cohort with detailed information on all pregnancies and deliveries in Jerusalem between 1974 and 1976. A subset of individuals participated in a follow-up study that took place between 2007 and 2009 in which they completed questionnaires and were physically examined at mean age of 32. A blood sample was additionally drawn from each participant, and AMH was measured in a sample of 239 women. The associations between each early-life factors, including birth weight, maternal pre-pregnancy weight, gestational weight gain (GWG), socioeconomic position at birth, and parental smoking during pregnancy, were assessed with AMH levels at the age of 32.Multivariable regression models were used to examine the associations with AMH, adjusting for potential confounders at birth and at the age of 32., Results: Low birth weight was significantly associated with lower ovarian reserve reflected by lower levels of AMH at age 32 (range 30-36), independent of other early-life factors and after adjusting for confounders (β = 0.180, p = 0.03)., Conclusions: This prospective study demonstrates the association of birth weight and adult ovarian reserve. Underlying mechanisms are yet to be fully understood., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Among the challenges presented by the SARS-CoV2 pandemic are those related to balancing societal priorities with averting threats to population health. In this exceptional context a group of Israeli physicians and public health scholars (multidisciplinary academic group on children and coronavirus [MACC]) coalesced, examining the role of children in viral transmission and assessing the necessity and consequences of restricted in-class education. Combining critical appraisal and analytical skills with public health experience, MACC advocated for safe and monitored school re-opening, stressing the importance of education as a determinant of health, continuously weighing this stance against evolving COVID-19-risk data. MACC's activities included offering research-based advice to government agencies including Ministries of Health, Finance, and Education. In a setting where government bodies were faced with providing practical solutions to both decreasing disease transmission and maintaining society's vital activities, and various advisors presented decision-makers with disparate views, MACC contributed epidemiological, clinical and health policy expertise to the debate regarding school closure as a pandemic control measure, and adaptations required for safe re-opening. In this paper, we describe the evolution, activities, policy inputs and media profile of MACC, and discuss the role of academics in advocacy and activism in the midst of an unprecedented public health crisis. A general lesson learned is that academics, based on the rigor of their scientific work and their perceived objectivity, can and should be mobilized to pursue and promote policies based on shared societal values as well as empiric data, even when considerable uncertainty exists about the appropriate course of action. Mechanisms should be in place to open channels to multidisciplinary academic groups and bring their input to bear on decision-making., (© 2021. The Author(s).)

Research on mortality associated with exposure to the Holocaust is relevant for a better understanding of the effects of genocides on survivors. To our knowledge, previous studies have not investigated the long-term cause-specific mortality of Holocaust survivors. We compared mortality rates among Israelis born in European countries controlled by the Nazis during World War II with those among Israelis of European descent who did not have this exposure. Records of 22,671 people (45% women; 5,042 survivors) from the population-based Jerusalem Perinatal Study (1964-1976) were linked to the Israeli Population Registry, which was updated through 2016. Cox models were used for analysis, with 2-sided tests of statistical significance. Risk of all-cause mortality was higher among exposed women (hazard ratio (HR) = 1.15, 95% confidence interval (CI): 1.05, 1.27) than in unexposed women. No association was found between Holocaust exposure and male all-cause mortality. In both sexes, survivors had higher cancer-specific mortality (HR = 1.17 (95% CI: 1.01, 1.35) in women and HR = 1.14 (95% CI: 1.01, 1.28) in men). Exposed men also had excess mortality due to coronary heart disease (HR = 1.39, 95% CI: 1.09, 1.77) and lower mortality from other known causes combined (HR = 0.86, 95% CI: 0.75, 0.99). In summary, experiencing the Holocaust was associated with excess all-cause and cancer-specific mortality in women and cancer- and coronary heart disease-specific mortality in men., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Israel is one of the first countries to incorporate chromosomal microarray analysis into routine prenatal care. We explored attitudes of Israeli healthcare professionals (HCPs) towards the disclosure of challenging findings: variants of uncertain clinical significance (VUS), susceptibility loci (SL) for neurodevelopmental disorders and variants associated with adult-onset (AO) conditions. Particularly, we sought their views on providing parental choice regarding the disclosure of these findings., Methods: Twenty-nine in-depth interviews were conducted with genetic counselors (n = 19), medical geneticists (n = 4), medical geneticists that are trained in and practice fetal medicine (n = 3), and fetal medicine experts (n = 3)., Results: Most participants (n = 24) supported parental choice regarding uncertain genetic information. Engaging parents in disclosure decisions allows avoidance from potentially anxiety-provoking information, practicing parental autonomy, and better preparation in cases where uncertain findings are identified. HCPs believed that given appropriate preparation, parents can make informed decisions. Four participants believed that disclosure should be based on professional judgment and one supported full-disclosure. Unlike VUS or SL, all interviewees agreed that in cases of medically actionable AO conditions, the benefit of disclosure outweighs the damage., Conclusion: HCPs attitudes are largely in-line with the Israeli practice of involving parents in disclosure decisions regarding uncertain information. This may mitigate disclosure dilemmas and allow personalized disclosure based on parents' views., (© 2021 John Wiley & Sons Ltd.)

Study Objectives: The stress imposed by the COVID-19 pandemic and ensuing social isolation could adversely affect sleep. As sleep problems may persist and hurt health, it is important to identify which populations have experienced changes in sleeping patterns during the pandemic and their extent., Methods: In Study 1, 3,062 responders from 49 countries accessed the survey website voluntarily between March 26 and April 26, 2020, and 2,562 (84%; age: 45.2 ± 14.5, 68% women) completed the study. In Study 2, 1,022 adult US responders were recruited for pay through Mechanical Turk, and 971 (95%; age 40.4 ± 13.6, 52% women) completed the study. The survey tool included demographics and items adapted from validated sleep questionnaires on sleep duration, quality and timing, and sleeping pills consumption., Results: In Study 1, 58% of the responders were unsatisfied with their sleep. Forty percent of the responders reported a decreased sleep quality vs before COVID-19 crisis. Self-reported sleeping pill consumption increased by 20% (P < .001). Multivariable analysis indicated that female sex, being in quarantine, and 31- to 45-years age group, reduced physical activity and adverse impact on livelihood were independently associated with more severe worsening of sleep quality during the pandemic. The majority of findings were reproduced in the independent cohort of Study 2., Conclusions: Changes imposed due to the pandemic have led to a surge in individuals reporting sleep problems across the globe. The findings raise the need to screen for worsening sleep patterns and use of sleeping aids, especially in more susceptible populations, namely, women and people with insecure livelihoods subjected to social isolation., (© 2021 American Academy of Sleep Medicine.)

Objectives: To investigate the effect of birth weight (BW) and maternal pre-pregnancy BMI (mBMI) on blood pressure (BP) in adolescence., Methods: A Population-based cohort of 11,729 births in Jerusalem during 1974-1976, with archival data on maternal and birth characteristics was performed. Measurements at age 17 were assessed and linear regression models were used to evaluate the associations of birth characteristics with BP outcomes., Results: BW was inversely associated with both systolic (SBP) and diastolic (DBP) BP at age 17 (SBP: B = - 0.829, p = 0.002; DBP: B = - 0.397, p = 0.033). The interaction term between BW and weight at age 17 was significant for DBP (p = 0.017) and pulse pressure (p = 0.005). mBMI yielded significant positive associations with BP, independent of BW., Conclusions for Practice: Our findings indicate that there are at least two distinct pathways linking early life characteristics with subsequent BP: Intrauterine growth, as reflected by BW and other genetic or environmental factors, reflected by mBMI and maternal education, contribute to offspring adolescent BP. These results warrant replication in other birth cohorts and underline the need to explore specific mechanisms that account for these associations.

Aims/hypothesis: There are established relationships between adiposity (obesity) and higher dementia risk, faster cognitive decline and associated neural injury. Type 2 diabetes is strongly linked to greater adiposity and has been consistently associated with neural injury and poor cognitive outcomes. However, although obesity is a major cause of type 2 diabetes, there is limited evidence on the association of adiposity with brain atrophy among individuals with type 2 diabetes., Methods: We examined the association of BMI (a measure of adiposity), and of long-term trajectories of BMI (three empirically identified groups of trajectories-'normal', 'overweight' and 'obese'-using SAS macro PROC TRAJ), with regional brain volume, in a sample of older individuals (aged 64-84) with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline Study (n = 198)., Results: Using linear regression, we found that greater BMI was associated with smaller volumes of the inferior frontal gyrus (IFG) (r = -0.25, p = 0.001) and the middle temporal gyrus (r = -0.19; p = 0.010) after adjusting for sociodemographic covariates and total intracranial volume. In addition, there were significant differences between BMI trajectory groups in IFG volume (F = 4.34, p = 0.014), such that a long-term trajectory of obesity was associated with a smaller volume. Additional adjustment for cardiovascular and diabetes-related potential confounders did not substantively alter the results. There were no associations of adiposity with superior frontal gyrus, middle frontal gyrus or total grey matter volumes., Conclusions/interpretation: In older adults with type 2 diabetes, long-term adiposity may have a detrimental impact on volume of brain regions relevant to cognitive functioning. Further studies to identify the underlying mechanisms are warranted. Graphical abstract.

Introduction: Scarce research is available regarding the association between interbirth intervals (IBI) and long-term maternal health outcomes, particularly cardiovascular disease (CVD) mortality. We aimed to assess whether IBIs were associated with all-cause, CVD-related and cancer-related mortality., Methods: We conducted a cohort study in the setting of the Jerusalem Perinatal Study. Women with at least two consecutive singleton live births in 1964-1976 (N=18 294) were followed through 2016. IBIs were calculated as the interval between women's first and second cohort birth. We estimated associations between IBIs and mortality using Cox's proportional hazards models, adjusting for age, parity, maternal education, maternal origin and paternal socioeconomic status. Date of last menstrual period was available for a subset of women. We assessed the interpregnancy interval (IPI) for these women and compared the models using IPI and IBI., Results: During 868 079 years of follow up (median follow-up: 49.0 years), 3337 women died. Women with IBIs <15 months had higher all-cause mortality rates (HR 1.18; 95% CI 1.05 to 1.33) compared to women with 33-month to 68-month IBIs (reference category). IBI and CVD mortality appeared to have a J-shaped association; IBIs of <15, 15-20, 21-2626-2632, 33-68 and ≥69 months had HRs of 1.44, 1.40, 1.33, 1.14, 1.00 and 1.30, respectively. No substantial association was found with cancer mortality. Models using IPIs and those using IBI were similar., Conclusion: Our results support the WHO recommendations for IPIs of ≥24 months and add additional evidence regarding long-term CVD mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Cardiometabolic traits pose a major global public health burden. Large-scale genome-wide association studies (GWAS) have identified multiple loci accounting for up to 30% of the genetic variance in complex traits such as cardiometabolic traits. However, the contribution of parent-of-origin effects (POEs) to complex traits has been largely ignored in GWAS. Family-based studies enable the assessment of POEs in genetic association analyses. We investigated POEs on a range of complex traits in 3 family-based studies. The discovery phase was carried out in large pedigrees from the Kibbutzim Family Study (n = 901 individuals) and in 872 parent-offspring trios from the Jerusalem Perinatal Study. Focusing on imprinted genomic regions, we examined parent-specific associations with 12 complex traits (i.e., body-size, blood pressure, lipids), mostly cardiometabolic risk traits. Forty five of the 11,967 SNPs initially found to have POE were evaluated for replication (p value < 1 × 10 -4 ) in Framingham Heart Study families (max n = 8000 individuals). Three common variants yielded evidence of POE in the meta-analysis. Two variants, located on chr6 in the HLA region, showed a paternal effect on height (rs1042136: β paternal  = -0.023, p value = 1.5 × 10 -8 and rs1431403: β paternal  = -0.011, p value = 5.4 × 10 -6 ). The corresponding maternally-derived effects were statistically nonsignificant. The variant rs9332053, located on chr13 in RCBTB2 gene, demonstrated a maternal effect on hip circumference (β maternal  = -4.24, p value = 9.6 × 10 -6 ; β paternal  = 1.29, p value = 0.23). These findings provide evidence for the utility of incorporating POEs into association studies of cardiometabolic traits, especially anthropometric traits. The study highlights the benefits of using family-based data for deciphering the genetic architecture of complex traits.

Objective: To examine the choices of women with both high-risk and low-risk pregnancies who are undergoing prenatal chromosomal microarray analysis in a clinical setting regarding three challenging types of findings: variants of uncertain clinical significance, susceptibility loci for neurodevelopmental disorders, and copy number variants associated with risks for adult-onset conditions. We assessed whether women's choices were associated with indications for testing or with one-on-one pretest genetic counseling., Methods: In this cross-sectional study, medical records of women who underwent invasive prenatal chromosomal microarray analysis testing (N=1,070) at Hadassah Medical Center between June 2017 and February 2018 were examined for testing indications, choices regarding chromosomal microarray analysis findings, and type of pretest genetic counseling. Multivariable analyses to assess associations with testing indication and prior genetic counseling were carried out using logistic regression models., Results: In total, 56% of women (n=593) chose to be informed of all three types of findings and 20% (n=218) chose not to be informed of any of the findings beyond high-penetrance childhood-onset pathogenic findings. Variants of uncertain clinical significance as a single choice was the least-selected finding (2.5%, n=27). Low-risk pregnancies (ie, those with normal biochemical screening and fetal ultrasound examinations) were associated with increased interest in receiving genetic information about adult-onset conditions (adjusted odds ratio [aOR] 1.7; 95% CI 1.18-2.33) and susceptibility loci (aOR 1.5; 95% CI 1.08-2.10)., Conclusion: Women with both high-risk and low-risk pregnancies were generally more likely to choose to receive additional genetic information, albeit differences in preferences depend on testing indication and type of pretest counseling.

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 ROH ) for >1.4 million individuals, we show that F ROH 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 ROH 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 ROH are confirmed within full-sibling pairs, where the variation in F ROH is independent of all environmental confounding.

Objective: To study the association between mode of delivery and offspring BMI in late adolescence in a large cohort that predated the obesity epidemic, and assess the role of maternal pre-pregnancy BMI (ppBMI) in this association., Study Design: We conducted a historical prospective study in the setting of the Jerusalem Perinatal Study (JPS), a population-based cohort that includes all 17,003 births to residents of West Jerusalem, between 1974 and 1976. Offspring's BMI at age 17 was obtained upon army recruitment and was available for 11,001 of cohort participants. The associations were examined using logistic regressions, adjusting for socio-demographic characteristics and for proxies for indication for C-Section birth. Analyses were then stratified by quartiles of ppBMI., Results: C-Section was associated with offspring overweight/obesity, with adjusted OR of 1.44 (95%CI:1.14-1.82). Significant interaction of ppBMI with mode of delivery was observed, such that the associations of C-Section with overweight/obesity were limited to the upper quartile of ppBMI (adjusted OR = 1.70, 95%CI:1.18-2.43). Restricting the analyses to singleton first births and excluding pregnancies complicated with toxemia and gestational diabetes yielded similar findings., Conclusions: C-Section was positively associated with being overweight/obese at age 17. Importantly, ppBMI modified this association, with a significant association between C-Section and overweight/obesity evident only among offspring born to mothers in the highest ppBMI quartile. In light of the growing rates of obesity in women of reproductive age, these results should be considered in patient-doctor shared decisions related to selection of mode of delivery, in the absence of a clear medical indication., Competing Interests: The authors have declared that no competing interests exist.

Genetic studies in isolated populations often increase power for identifying loci associated with complex diseases and traits. We present here the Kibbutzim Family Study (KFS), aimed at investigating the genetic basis of cardiometabolic traits in extended Israeli families characterized by long-term social stability and a homogeneous environment. Extensive information on cardiometabolic traits, as well as genome-wide genotypes, were collected on 901 individuals. We observed that most KFS participants were of Ashkenazi Jewish (AJ) genetic origin, confirmed a recent severe bottleneck in the AJ recent history, and detected a subtle within-AJ population structure. Focusing on genetic variants relatively common in the KFS but very rare in Europeans, we observed that AJ-enriched variants appear in cancer-related pathways more than expected by chance. We conducted an association study of the AJ-enriched variants against 16 cardiometabolic traits, and found seven loci (24 variants) to be significantly associated. The strongest association, which we also replicated in an independent study, was between a variant upstream of MSRA (frequency ≈1% in the KFS and nearly absent in Europeans) and weight (P = 3.6∙10 -8 ). In conclusion, the KFS is a valuable resource for the study of the population genetics of Israel as well as the genetics of cardiometabolic traits.