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Parent-of-origin effects in the life-course evolution of cardio-metabolic traits

29 Oct 2021-medRxiv (Cold Spring Harbor Laboratory Press)-
TL;DR: In this article, the authors investigated heritability and parent-of-origin effects on cardiometabolic and anthropometric traits in a birth-cohort with serial measurements to assess if these effects manifested at an early age.
Abstract: Objective: Human traits are heritable, and some of these including metabolic and lipid phenotypes show preferential parental transmissions, or parent-of-origin effects. These have been mostly studied in populations comprising adults. We aimed to investigate heritability and parent-of-origin effects on cardiometabolic and anthropometric traits in a birth-cohort with serial measurements to assess if these effects manifested at an early age. Research design and methods: We investigated heritability and parent-of-origin effects on cardiometabolic and anthropometric traits in the Pune Maternal Nutrition Study (PMNS) wherein offspring and parents were studied from birth and followed-up for 18 years. Heritability was estimated by calculating association between mid-parental phenotypes and offspring. Maternal and paternal effects on offspring phenotype were modelled by regression after adjusting for age, sex and BMI. Parent-of-origin effects were calculated by the difference between maternal and paternal effects. Results: Anthropomorphic traits and cardiometabolic traits were robustly heritable. Parent-of-origin effects were observed for glycemic traits at both 6- and 12-years, with a paternal effect at 6-years which transitioned to a maternal effect at 12-years. For insulin and HOMA-S, a negative maternal effect transitioned to a positive one at 12-years. For HOMA-B, a paternal effect at 6- years transitioned to a maternal one at 12-years. Lipid traits consistently showed stronger maternal influence while anthropometric traits did not show any parental biases. Conclusions: Our study highlights that parental programming of cardiometabolic traits is evident from early childhood and can transition during puberty. Further studies are needed to determine the mechanisms of underlying such effects.

Summary (3 min read)

Introduction

  • Human traits and diseases are a consequence of a complex interplay between genetics and environment.
  • In a classic Mendelian pattern of transmission, a trait can be contributed by both the parents equally; it is also possible that these may be inherited preferentially from one of the parents while the contribution of the other parent can be low, neutral or even opposite.
  • Parent-of-origin as well as sex-specific parental effects were observed for anthropometric measures, insulin secretion and all cholesterol levels (1; 2; 11).
  • These studies were of cross-sectional design in adult offspring; however, given the role of early life programming in risk of cardiometabolic disorders in later life, it is possible that these parental effects manifest at an early age.

Cohort characteristics

  • The Pune Maternal Nutrition Study (PMNS) was established in 1993 in six villages near Pune, to prospectively study associations of maternal nutritional status with fetal growth and later diabetes risk in the offspring.
  • Between 1994 and 1996, those who became pregnant (F0 generation) were recruited into the study.
  • The children's (F1 generation) growth was measured in utero, at birth and 6 monthly thereafter, and body composition and glucose-insulin indices were measured 6-yearly (Table 1 , Supplementary Table 1 ).
  • Ethical permission and informed consent were obtained for the study.
  • Parents gave written consent; children under 18 years of age gave written assent, and written consent after reaching 18 years.

Anthropometric and clinical measurements in parents and offspring

  • Newborn anthropometry including weight, length, abdominal circumference and skinfolds was carried out within 72 hours of birth.
  • Comprehensive assessments of body composition and glucose and insulin concentrations were made at 6, 12 and 18 years.
  • Participants arrived at the Diabetes Unit (KEM Hospital, Pune) the evening before, had a standardized dinner, and fasted overnight.
  • At 6 years, an oral glucose tolerance test (OGTT) was performed, using 1.75g/kg of anhydrous glucose, followed by further samples at 30 and 120 minutes.
  • BMI was calculated using standard formula [weight (kg)/square of height (m)] and WHR was calculated as waist circumference (cm) / hip circumference (cm).

Statistical analysis

  • Heritability and parent-of-origin effects were assessed between F0 and F1 generation across different time points (Pre-pregnancy, At birth, 6yrs, 12yrs, 18yrs) in PMNS cohort for anthropometric and glycemic traits.
  • For this, the skewed variables were log transformed, and all variables were standardized (mean zero, standard deviation unity) adjusted for age and gender to facilitate the comparison between variables.
  • Heritability was estimated using regression models adjusted for age and gender expressed in ß and p-value.
  • Parent-of-origin effects were tested by computing the difference in maternal and paternal regression coefficients using the formula [(b1-b2) / sqrt (seb1**2 + seb2**2 -cov(b1*b2))] expressed in Z and corresponding p value.

Heritability of anthropometric and metabolic traits

  • Offspring's weight, height and BMI were significantly associated with corresponding midparental measures with coefficients ranging between 0.13 to 0.24 at birth.
  • Offspring measurements of waist and hip circumference, WHR, fat and lean mass (DXA) at 6-years also showed significant association with mid-parental measures.
  • These heritability estimates were similar for sons and daughters (Supplementary Table 3 ).
  • At 12-years, similar associations were observed for the aforementioned measures with addition of HOMA2S (ranging from 0.19 to 0.31).
  • Triglyceride, total cholesterol and HDL levels were significantly heritable at 6 and 12 years.

Parent-of-origin and sex-specific parental effects on cardiometabolic traits

  • The authors next examined if there was a stronger association between the trait of the offspring and the trait of each of the parents specifically.
  • If offspring showed a stronger association with the mother's traits compared to the father's, this would indicate a maternal effect and likewise for the paternal effect.
  • If there were a significant difference between the maternal and paternal effects, this is indicative of the parent-of-origin effect.
  • While offspring anthropometry was significantly associated with that of each of the parents, no significant parent-of-origin effects were observed either in all offspring or for sons and daughters separately (Table 2 , Supplementary Table 5 ), also known as Anthropometry.

Glucose and insulin indices:

  • Fasting glucose concentrations in the offspring were positively associated with that of the mother's as well as the father's glucose concentrations both at 6and 12-years.
  • For insulin and its indices, sons showed a significant negative maternal association at 6-years which shifted to a positive one at 12-years, however the parent-of-origin effects were significant only at 6-years.
  • In the daughters, no parental associations were seen at 6-years, whereas, positive maternal associations and significant parent-of-origin effects were seen at 12-years (Table 3 ).
  • Total and HDL cholesterol levels in the offspring showed significantly stronger positive associations with mother compared to father at 6 and 12 years in all offspring as well as when analysed separately for sons, also known as Lipid levels.
  • The parental differences were not significant in daughters at either 6 or 12-years.

Discussion

  • By harnessing the potential of a birth cohort, the authors observed strong parent-of-origin effects on metabolic but not anthropometric traits starting from early life.
  • Though previous studies hinted at such effects for glucose and insulin levels and their indices (1; 2; 11), their results robustly confirm these parental specific associations.
  • Several theories have been proposed to explain the evolutionary origins of parent-of-origin effects which are a consequence of genomic imprinting.
  • During postnatal life, maternal and paternal associations with offspring anthropometry were similar.
  • RBP and CSY are the guarantors of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

* Maximum numbers available are mentioned. Not all data may be available on the mentioned numbers.

  • Population description for parents and offspring of the Pune Maternal Nutrition Study (PMNS) for visits at offspring ages 6-, 12-and 18-years.
  • Association between offspring anthropometry measures with that of each of the parents are presented as beta values and se.
  • Differences between maternal and paternal effects are presented as Z scores and p-values.

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1
Parent-of-origin effects in the life-course evolution of cardio-metabolic traits
Short running title: Parent-of-origin effects on metabolic traits
Rucha Wagh MSc
1
, Pooja Kunte MSc
1
, Chittaranjan S Yajnik MD
1*
, Rashmi B Prasad PhD
2,
3*
1
Diabetes Unit, Kamalnayan Bajaj Diabetology Research Centre, King Edward Memorial
Hospital and Research Centre, Pune 411011, India.
2
Department of Clinical Sciences, Diabetes and Endocrinology, CRC, Lund University,
Malmö SE-205 02, Sweden
3
Institute of Molecular Medicine Finland, FIMM, Helsinki University, Helsinki 00290,
Finland
*equal contribution
Corresponding author:
Rashmi B Prasad, Department of Clinical Sciences, Diabetes and Endocrinology,
CRC, Lund University, S-205 02 Malmö, Sweden. E-mail: rashmi.prasad@med.lu.se
Telephone number: +46 40 39 12 14, +46 704640275
Word count:
Abstract: Word limit: 250 words: 248 words
Main text: Word limit: 4000 words, 40 references: 2665, 35 references
Number of tables and figures: Limit: Max 4 figures /tables: 1 figure, 3 tables
Number of supplementary tables and figures: 5 Supplementary Tables
All rights reserved. No reuse allowed without permission.
perpetuity.
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
The copyright holder for thisthis version posted October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265599doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

2
Abstract
Objective: Human traits are heritable, and some of these including metabolic and lipid
phenotypes show preferential parental transmissions, or parent-of-origin effects. These have
been mostly studied in populations comprising adults. We aimed to investigate heritability and
parent-of-origin effects on cardiometabolic and anthropometric traits in a birth-cohort with
serial measurements to assess if these effects manifested at an early age.
Research design and methods: We investigated heritability and parent-of-origin effects on
cardiometabolic and anthropometric traits in the Pune Maternal Nutrition Study (PMNS)
wherein offspring and parents were studied from birth and followed-up for 18 years.
Heritability was estimated by calculating association between mid-parental phenotypes and
offspring. Maternal and paternal effects on offspring phenotype were modelled by regression
after adjusting for age, sex and BMI. Parent-of-origin effects were calculated by the difference
between maternal and paternal effects.
Results: Anthropomorphic traits and cardiometabolic traits were robustly heritable. Parent-of-
origin effects were observed for glycemic traits at both 6- and 12-years, with a paternal effect
at 6-years which transitioned to a maternal effect at 12-years. For insulin and HOMA-S, a
negative maternal effect transitioned to a positive one at 12-years. For HOMA-B, a paternal
effect at 6- years transitioned to a maternal one at 12-years. Lipid traits consistently showed
stronger maternal influence while anthropometric traits did not show any parental biases.
Conclusions: Our study highlights that parental programming of cardiometabolic traits is
evident from early childhood and can transition during puberty. Further studies are needed to
determine the mechanisms of underlying such effects.
All rights reserved. No reuse allowed without permission.
perpetuity.
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
The copyright holder for thisthis version posted October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265599doi: medRxiv preprint

3
Introduction
Human traits and diseases are a consequence of a complex interplay between genetics and
environment. Assessment of heritability provides information on the contribution of the genetic
component to the total phenotypic variation in a population. Anthropometric and metabolic
traits have thus far been shown to be heritable to varying degrees (1; 2). Genetic association
studies have identified a number of variants associated with these traits, however, the
proportion of heritability attributed to these variants was rather limited (3; 4).
In a classic Mendelian pattern of transmission, a trait can be contributed by both the parents
equally; it is also possible that these may be inherited preferentially from one of the parents
while the contribution of the other parent can be low, neutral or even opposite. Such effects
whereby the expression of the phenotype in the offspring depends upon which parent they are
inherited from, are termed as parent-of-origin effects. These can be attributed to genetic
imprinting, intrauterine effects, or maternally inherited mitochondrial genes (5). The
significance of such effects in aetiology of type 2 diabetes and obesity has been emphasized
previously (6). Type 2 diabetes shows a preferential maternal transmission (2; 7), and a
substantial component may originate in the intrauterine period. Several studies have
demonstrated that early life exposures can influence developmental programming and increase
risk to cardiometabolic disorders in later life (8-10).
Parent-of-origin as well as sex-specific parental effects were observed for anthropometric
measures, insulin secretion and all cholesterol levels (1; 2; 11). For instance, sons of diabetic
mothers had lower insulin concentrations compared to those of diabetic fathers, while
daughters of diabetic mothers had the lowest high-density lipoprotein (HDL) levels (2).
These studies were of cross-sectional design in adult offspring; however, given the role of early
life programming in risk of cardiometabolic disorders in later life, it is possible that these
parental effects manifest at an early age. The Pune Maternal Nutrition Study (PMNS), a well-
characterised prospective birth cohort provides a unique opportunity to study heritability and
parent-of-origin effects in parent-offspring trios in a life-course model. In this study, we
investigated the heritability and parent-of-origin effects of anthropometric, glycemic and
insulin related traits and lipid traits in the PMNS birth cohort with follow-up from birth through
puberty till adulthood. Parent-offspring associations and transitions of parental specific effects
across childhood was assessed.
All rights reserved. No reuse allowed without permission.
perpetuity.
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
The copyright holder for thisthis version posted October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265599doi: medRxiv preprint

4
Methods
Cohort characteristics
The Pune Maternal Nutrition Study (PMNS) (Figure 1) was established in 1993 in six villages
near Pune, to prospectively study associations of maternal nutritional status with fetal growth
and later diabetes risk in the offspring. Married, non-pregnant women (N=2,466) were followed
up. Between 1994 and 1996, those who became pregnant (F0 generation) were recruited into
the study. The children’s (F1 generation) growth was measured in utero, at birth and 6 monthly
thereafter, and body composition and glucose-insulin indices were measured 6-yearly (Table
1, Supplementary Table 1). Ethical permission and informed consent were obtained for the
study. The study was approved by village leaders and the KEM Hospital Research Centre
Ethics Committee. Parents gave written consent; children under 18 years of age gave written
assent, and written consent after reaching 18 years.
Anthropometric and clinical measurements in parents and offspring
Newborn anthropometry including weight, length, abdominal circumference and skinfolds was
carried out within 72 hours of birth.
Comprehensive assessments of body composition and glucose and insulin concentrations were
made at 6, 12 and 18 years. Participants arrived at the Diabetes Unit (KEM Hospital, Pune) the
evening before, had a standardized dinner, and fasted overnight. In the morning, a fasting blood
sample was collected. At 6 years, an oral glucose tolerance test (OGTT) was performed, using
1.75g/kg of anhydrous glucose, followed by further samples at 30 and 120 minutes. At 12
years, only a fasting sample was collected. At 18 years a full OGTT (75g anhydrous glucose)
was repeated.
Glucose was measured by the glucose oxidase/peroxidase method, and specific insulin by
ELISA (Supplementary Table 2). Homeostatic model assessment for insulin sensitivity
(HOMA-S), beta-cell function (HOMA) and insulin resistance (HOMA-R) were calculated
using data from the fasting samples and the iHOMA2 website
((https://www.phc.ox.ac.uk/research/technology-outputs/ihoma2) (12). Disposition index
cell function adjusted for insulin sensitivity) was calculated as HOMA-S*HOMA-β.
Total fat and lean mass and body fat% were measured by Dual Energy X-ray Absorptiometry
scanner. (Lunar DPX-IQ 240 pencil beam machine, Lunar Corporation, Madison, WI, USA).
Body size (anthropometry) and glucose tolerance (75 g OGTT) were measured in both parents
at the time of initial visit and at 6 year follow up. Body size and only a fasting blood test was
All rights reserved. No reuse allowed without permission.
perpetuity.
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
The copyright holder for thisthis version posted October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265599doi: medRxiv preprint

5
available at 12-year follow-up. BMI was calculated using standard formula [weight (kg)/square
of height (m)] and WHR was calculated as waist circumference (cm) / hip circumference (cm).
Statistical analysis
Heritability and parent-of-origin effects were assessed between F0 and F1 generation across
different time points (Pre-pregnancy, At birth, 6yrs, 12yrs, 18yrs) in PMNS cohort for
anthropometric and glycemic traits. For this, the skewed variables were log transformed, and
all variables were standardized (mean zero, standard deviation unity) adjusted for age and
gender to facilitate the comparison between variables. Heritability was estimated using
regression models adjusted for age and gender expressed in ß and p-value. Parent-of-origin
effects were tested by computing the difference in maternal and paternal regression coefficients
using the formula [(b1-b2) / sqrt (seb1**2 + seb2**2 cov(b1*b2))] expressed in Z and
corresponding p value.
Results
Heritability of anthropometric and metabolic traits
To investigate the proportion of offspring phenotypic trait attributable to parent phenotype
variation, we calculated heritability estimates of anthropometric and metabolic traits measured
in ~700 parent-offspring trios in the PMNS cohort at birth, 6, 12 and 18 years of age (Table 1).
Offspring’s weight, height and BMI were significantly associated with corresponding mid-
parental measures with coefficients ranging between 0.13 to 0.24 at birth. Moreover, there was
an upward trend in effect size across timepoints increasing to 0.36 to 0.51 at 6-years, 0.44 to
0.52 at 12-years, and 0.41 to 0.60 at 18-years (Supplementary Table 3). Offspring
measurements of waist and hip circumference, WHR, fat and lean mass (DXA) at 6-years also
showed significant association with mid-parental measures. These measurements were
available in parents only at 6y (Supplementary Table 3). These heritability estimates were
similar for sons and daughters (Supplementary Table 3).
Offspring concentrations of fasting glucose and insulin, as well as HOMA 2B showed a
significant association with corresponding mid-parental measures at 6 years (ranging from 0.10
to 0.41). At 12-years, similar associations were observed for the aforementioned measures with
addition of HOMA2S (ranging from 0.19 to 0.31). This trend was consistent for sons and
daughters (Supplementary Table 4).
All rights reserved. No reuse allowed without permission.
perpetuity.
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
The copyright holder for thisthis version posted October 29, 2021. ; https://doi.org/10.1101/2021.10.28.21265599doi: medRxiv preprint

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Q1. What are the contributions in "Parent-of-origin effects in the life-course evolution of cardio-metabolic traits short running title: parent-of-origin effects on metabolic traits" ?

Preprint ( which was not certified by peer review ) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted October 29, 2021.