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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2014 May 30;99(8):2961–2966. doi: 10.1210/jc.2013-4338

Parent-of-Origin Effects on Glucose Homeostasis in Polycystic Ovary Syndrome

Kristen Kobaly 1, Priyathama Vellanki 1, Ryan K Sisk 1, Loren Armstrong 1, Ji Young Lee 1, Jungwha Lee 1, M Geoffrey Hayes 1, Margrit Urbanek 1, Richard S Legro 1, Andrea Dunaif 1,✉
PMCID: PMC4121025  PMID: 24878041

Abstract

Context:

Polycystic ovary syndrome (PCOS) is a highly heritable complex trait. Parents of affected women have reproductive and metabolic phenotypes.

Objective:

We tested the hypothesis that there are parental effects on the heritability of fasting dysglycemia in women with PCOS.

Design and Setting:

This was a cross-sectional study at an academic medical center.

Participants:

Participants included 367 women with PCOS and their parents (1101 total subjects).

Main Outcome Measures:

We compared maternal and paternal contributions to heritability of fasting dysglycemia and to transmission of the PCOS susceptibility allele of D19S884 within the fibrillin-3 gene (D19S884-A8) on fasting dysglycemia.

Results:

Fathers had higher fasting glucose levels, prevalence of fasting dysglycemia and proinsulin to insulin molar ratios (P < .0001), a marker of defective insulin processing, compared with mothers. Heritability of fasting dysglycemia was significant in PCOS families (h2 = 37%, SE = 10%, P = .001). Maternal heritability (h2 = 51%, SE = 15%, P = .0009) was higher than paternal heritability (h2 = 23 %, SE = 23%, P = .186) of fasting dysglycemia after adjustment for age and body mass index. Within dysglycemic probands, there was increased maternal compared with paternal transmission of D19S884-A8 (maternal 84% vs paternal 45%, χ2 = 6.51, P = .011).

Conclusions:

There was a sex difference in the parental metabolic phenotype with fathers having an increased risk of fasting dysglycemia and evidence for pancreatic β-cell dysfunction compared with mothers. However, only maternal heritability had significant effects on the prevalence of fasting dysglycemia in women with PCOS. Furthermore, there were maternal parent-of-origin effects on transmission of D19S884-A8 probands with fasting dysglycemia. These findings suggest that maternal factors, genetic and perhaps epigenetic, contribute to the metabolic phenotype in affected women.

Polycystic ovary syndrome (PCOS) is among the most common disorders of reproductive-aged women with the classic syndrome of hyperandrogenism and chronic anovulation affecting ∼7% of this population (1). PCOS is associated with metabolic abnormalities including insulin resistance, pancreatic β-cell dysfunction, obesity, dyslipidemia, and an increased risk for type 2 diabetes (T2D) (1). Furthermore, the syndrome is highly heritable with concordance rates of 71% in monozygotic and 38% in dizygotic twins (1) compared with concordance rates of 35% to 58% in monozygotic and 17% to 20% in dizygotic twins for T2D (2, 3). Approximately 40% of reproductive-age sisters of women with PCOS are affected with the reproductive phenotype of hyperandrogenemia (4), whereas only 15% to 25% of first-degree relatives of patients with T2D have impaired glucose tolerance or T2D (5). In addition, mothers and fathers of women with PCOS have an increased prevalence of T2D (6), metabolic syndrome, and dyslipidemia (1).

The familial clustering of PCOS and its associated phenotypes suggests a genetic contribution to these traits. Consistent with this hypothesis, several susceptibility loci for PCOS have been reproducibly mapped (7). One such locus that we mapped, a variant in the dinucleotide repeat marker D19S884, located within intron 55 of the fibrillin-3 gene (FBN3), is also associated with increased fasting insulin levels in affected women and with increased proinsulin to insulin molar ratios, a marker of defective pancreatic β-cell insulin processing, in their brothers (8). These findings suggest that there are sex-specific gene effects on the metabolic phenotype. In addition, environmental factors, such as obesity and hyperandrogenemia, contribute to metabolic risk in PCOS (1).

In T2D, there is evidence for maternal transmission (9) of impaired glucose homeostasis. Inheritance of maternal mitochondrial genes (10), gene imprinting (11), and intrauterine environment (12) have been implicated as possible modes of maternal transmission. However, parental influences on the metabolic phenotype in PCOS have not been examined. This question is of considerable importance because mothers and fathers of these women have abnormal metabolic phenotypes (1, 13–16). Furthermore, pregnant women with PCOS have increased circulating androgen and insulin levels (13) as well as an increased risk of gestational diabetes (17) that could result in long-term metabolic effects on their offspring (12). To gain insight into heritable contributors to metabolic features of PCOS, we performed this study to test the hypothesis that there are sex-specific parental effects on the development of fasting dysglycemia in women with PCOS.

Subjects and Methods

Study subjects

The study was approved by the Institutional Review Boards of the Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Brigham and Women's Hospital, Boston, Massachusetts; and the Pennsylvania State University College of Medicine, Hershey, Pennsylvania. Written informed consent was obtained from all subjects. We studied 367 women with PCOS whose parents both participated in our study (total n = 1101). All subjects were Caucasians of European ancestry. Detailed reproductive and medical histories were obtained by validated questionnaires (4, 8, 15, 16). Women with PCOS were not taking any oral contraceptive medications for at least 3 months before the study. Subjects receiving antidiabetic (3 probands, 43 fathers, 31 mothers) medications were classified as dysglycemic. Parents were not on other medications known to affect glucose metabolism for at least 1 month before the study, except for postmenopausal hormone therapy (HT), which 91 mothers were receiving.

In all, 647 subjects were studied off-site and 454 subjects were studied on-site. Off-site phenotyping methods, including waist circumference measurements (76 probands, 148 fathers, 136 mothers), have been described previously (4, 8, 15, 16). Blood samples for testosterone, dehydroepiandrosterone sulfate, SHBG, glucose, insulin, and proinsulin levels were obtained in the morning after a 3-day 300-g carbohydrate per day diet and an overnight fast (4, 8, 15, 16). Probands all fulfilled criteria for the National Institutes of Health PCOS phenotype with biochemically documented androgen excess and ovulatory dysfunction (≤ 6 menses/y) and the exclusion of other hyperandrogenic disorders of the pituitary, ovary, or adrenals (1). Accordingly, these probands also fulfilled Rotterdam and androgen excess-PCOS criteria for PCOS (1). Phenotype and genotype data from the probands and their parents have been previously reported (4, 8, 15, 16, 18).

Assays, DNA extraction, and genotyping

Fasting glucose, insulin, and proinsulin levels were measured as reported (8). DNA extraction and genotyping of D19S884 was performed as reported (8). Genotyping of D19S884 failed due to technical reasons in 4 women with PCOS, 22 fathers, and 17 mothers. The PCOS susceptibility allele of D19S884 was designated as D19S884-A8. Because there were very few subjects who were homozygous carries of D19S884-A8, both homozygous and heterozygous carriers were designated as D19S884-A8+. Subjects with all other alleles of D19S884 were designated as D19S884-A8−.

Data analyses

Body mass index (BMI) was classified as nonobese (<25.0 kg/m2), overweight (25.0–29.9 kg/m2), or obese (≥30 kg/m2). Subjects were assigned a glycemic status according to the American Diabetes Association classification of fasting glucose levels (19) with fasting glucose <100 mg/dL considered euglycemia and fasting glucose ≥100 mg/dL considered dysglycemia. Individuals with fasting dysglycemia were further stratified for some analyses as follows: fasting glucose ≥100 mg/dL and < 126 mg/dL indicates impaired fasting glucose, and fasting glucose ≥126 mg/dL indicates T2D. All subjects who self-reported a history of T2D (excluding gestational diabetes mellitus) or who were taking medications for treatment of diabetes (n = 77) were considered to have dysglycemia, regardless of their fasting glucose level.

Two-tailed unpaired t tests or Wilcoxon rank sum tests were used for 2 group comparisons, depending on the normality of the data. Probands were younger and had higher BMIs than either parent. However, the assumptions for the application of analysis of covariance were not fulfilled because, even after multiple transformations, the residuals of the endpoint data were not normally distributed. Accordingly, Kruskal-Wallis tests were used to compare probands, mothers, and fathers. The independent impact of age and BMI were not controlled for in these analyses. Wilcoxon rank sum tests were applied for post hoc tests with the level of α adjusted for multiple comparisons using a Bonferroni correction, ie, proband vs mother, proband vs father, mother vs father, with P = .05 ÷ 3 = .0167, and χ2 tests were used for categorical variables.

Our primary endpoint was the heritability of the dysglycemia. Fasting glucose levels were dichotomized into 2 categories: euglycemia and dysglycemia. Heritability estimates (h2) for this dichotomous trait were calculated using SOLAR (Sequential Oligogenic Linkage Analysis Routines) software version 4.2.7 (Southwest Foundation for Biomedical Research, 2009). The parameter h2 is the narrow-sense heritability and is equal to the proportion of phenotypic variance that is attributed to additive genetic variance (20). For dichotomous traits, SOLAR uses a threshold model to calculate the proportion of phenotypic variance attributed to genetic variance (21). A maximum likelihood model was used to test the significance of h2 against the null model (h2 = 0). To analyze paternal effects, h2 was calculated by setting phenotypic information unknown for mothers. Phenotypic information was set to unknown for fathers to calculate maternal effects. The heritability analyses were adjusted for parental and proband's age and BMI as continuous covariates. Heritability estimates, h2, are expressed as percentage ± SE.

The transmission disequilibrium test (8) was used to compare maternal and paternal transmission of D19S884-A8 in dysglycemic and nondysglycemic probands. For this analysis, families were excluded if both parents were noncarriers of D19S884-A8 (n = 153) or could not be reliably genotyped (n = 16). Of the remaining 198 families, there were 7 families where genotyping failed for one of the parents (6 fathers, 1 mother). In these 7 families, the family was classified as a nontransmission of D19S884-A8 from the known parent, if the proband was a noncarrier for D19S884-A8 and the known parental genotype was heterozygous for D19S884-A8. The family was classified as a transmission of D19S884-A8 from the known parent, if the proband was a homozygous carrier for D19S884-A8 and known parental genotype was heterozygous for this allele.

Statistical analyses, other than heritability estimates, were performed using SAS software for Windows, version 9.3 (SAS Institute). All continuous data are reported as the mean ± SD or median with 25th to 75th interquartile range in parentheses, depending on the normality of the data. The level of α was set at .05 and adjusted as outlined for multiple comparisons.

Results

Probands were younger than fathers (P < .0001) and mothers (P < .0001); fathers were significantly older (P < .0001) than mothers (Table 1). Probands had significantly higher BMI than fathers and mothers (both P < .0001), but BMI did not differ between fathers and mothers (Table 1). The prevalence of obesity was significantly increased in probands compared with fathers and mothers (both P < .0001). The prevalence of overweight and obesity differed in fathers compared with mothers (P = .0007); fathers had a similar prevalence of overweight and obesity, whereas mothers had an increased prevalence of obesity compared with overweight (Table 1). Probands had significantly higher waist circumference compared with mothers (P < .0001) but not fathers; fathers had significantly higher waist circumference compared with mothers (P < .0001) (Table 1).

Table 1.

Clinical and Metabolic Characteristics of PCOS Probands and Parentsa

Variable Probands Fathers Mothers P
Age, y 28 (24–31) (n = 367) 56 (51–62)a,c (n = 367) 54 (49–59)b (n = 367) <.0001
BMI, kg/m2 35.7 (28.6–41.3) (n = 367) 29.4 (26.5–32.5)a (n = 367) 29.3 (25.2–34.7)b (n = 367) <.0001
Nonobese, overweight, obese, % 13, 17, 70 (n = 367) 13, 43, 44 (n = 367) 22, 32, 47 (n = 367) <.0001
Waist circumference, cm 102 (86–117) (n = 289) 103 (94–111)c (n = 241) 91 (80–104)b (n = 255) <.0001
Fasting glucose, mg/dL 89 (83–96) (n = 367) 98 (90–112)a,c (n = 367) 93 (86–102)b (n = 367) <.0001
Fasting dysglycemia prevalence, % 21 (n = 367) 43a,d (n = 367) 30 (n = 367) <.0001
Fasting insulin, μU/mL 23 (15–34) (n = 363) 15 (12–25)a (n = 363) 15 (11–22)b (n = 359) <.0001
Proinsulin to insulin molar ratio 0.11 (0.08–0.16) (n = 350) 0.15 (0.11–0.22)a,c (n = 352) 0.12 (0.09–0.18)e (n = 348) <.0001
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a

Data are expressed as median (25th–75th interquartile range) or percentage; P value, Kruskal-Wallis test; aP <.0001 Probands vs. Fathers;

b

P <.0001 Probands vs. Mothers;

c

P <.0001 Fathers vs. Mothers;

d

P <.0167 Fathers vs. Mothers;

e

P = 0.00463 Probands vs. Mothers.

Fathers had significantly higher fasting glucose levels than mothers (P < .0001) and probands (P < .0001); mothers had significantly higher fasting glucose levels than probands (P < .0001) (Table 1). The prevalence of fasting dysglycemia was higher in fathers (P < .0167) compared with mothers and probands (Table 1). When individuals with fasting dysglycemia were stratified by glucose tolerance category, impaired fasting glucose and T2D were present in 15% and 6% of probands, 16% and 14% of mothers, and 23% and 19% of fathers, respectively. Probands had significantly higher fasting insulin levels than fathers and mothers (both P < .0001), whereas there were no differences in fasting insulin levels between fathers and mothers (Table 1). Proinsulin to insulin molar ratios were significantly higher in fathers compared with both mothers (P < .0001) and probands (P < .0001); mothers had significantly higher proinsulin to insulin molar ratios (P = .00463) compared with probands (Table 1).

Heritability for fasting dysglycemia was significant (h2 = 37%, SE = 10%, P = .001) when both parents were included in the analysis. However, this heritability was accounted for by stronger maternal compared with paternal heritability of fasting dysglycemia (maternal h2 = 51%, SE = 15%, P = .0009; paternal h2 = 23%, SE = 23%, P = .186). Neither the prevalence of fasting dysglycemia nor fasting glucose levels or proinsulin to insulin molar ratios differed in D19S884-A8+ compared with D19S884-A8− probands (data not shown). There was a trend toward higher fasting insulin levels in D19S884-A8+ probands (D19S884-A8+, 29 ± 18 μU/mL, vs D19S884-A8−, 25 ± 14 μU/mL, P = .1061). The prevalence of fasting dysglycemia, fasting glucose and insulin levels, and proinsulin to insulin molar ratios did not differ by genotype in D19S884-A8+ compared with D19S884-A8− mothers or fathers (data not shown).

Of the 198 families included in parent-of-origin analysis of transmission of D19S884-A8, fasting dysglycemia was present in 21% of probands, 43% of fathers, and 30% of mothers. In probands with fasting dysglycemia, maternal transmission of D19S884-A8 was significantly higher (P = .011) than paternal transmission of this allele (Table 2). In probands without fasting dysglycemia, maternal and paternal transmission of D19S884-A8 did not differ (Table 2).

Table 2.

Parent-of-Origin Effects on Transmission of D19S884-A8

Glycemic Status of Proband T (n) Non-T (n) Total (n) Transmission Frequency, % χ2 P
Dysglycemia (n = 44)
    Maternal 16 3 19 84
    Paternal 9 11 20 45 6.51 .011
Euglycemia (n = 154)
    Maternal 38 33 71 54
    Paternal 40 31 71 56 0.11 .736
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Abbreviation: T, number of transmissions of D19S884-A8.

Discussion

There was greater maternal compared with paternal heritability of fasting dysglycemia in women with PCOS, despite a higher prevalence of paternal fasting dysglycemia. Furthermore, there were maternal parent-of-origin effects on transmission of D19S884-A8 to probands with fasting dysglycemia. The greater maternal heritability as well as the maternal parent-of-origin effects suggest that maternal factors contribute to the heritability of fasting dysglycemia in PCOS. These observations are consistent with those in non-PCOS populations where evidence for maternal heritability of T2D (9, 22, 23) and fasting glucose levels (24) have been reported. Although extreme caution must be exercised when comparing heritability estimates because they are by definition population-specific (20), similar heritability estimates for fasting dysglycemia, 38%, to those found in our study were reported in a non-PCOS population (25).

The intrauterine environment could contribute to maternal heritability of fasting dysglycemia (12). Offspring of mothers with pregestational and gestational diabetes have increased rates of obesity and impaired glucose tolerance (12). Maternal obesity is also associated with an increased prevalence of metabolic syndrome in offspring (26). Women with PCOS are frequently obese (1) and have increased rates of gestational diabetes (17). PCOS is highly heritable (1, 27), and we have found that a substantial portion of mothers are also affected (15). Accordingly, gestational diabetes and obesity in mothers who had PCOS could contribute to increased maternal heritability of metabolic abnormalities (12, 26)

Alternatively, it is possible that other factors in the intrauterine environment contribute to the heritability of PCOS. Prenatal exposure to androgens can cause a complete phenocopy of metabolic as well as reproductive features of PCOS in animal models (28). Pregnant women with PCOS have higher circulating androgen levels (13). Thus, intrauterine androgen excess could play a role in the pathogenesis of PCOS (28) because mothers may also be affected (15). However, placental aromatase is an effective barrier to maternal androgens, and accurate androgen assays have not found increased cord blood androgen levels in the newborns of mothers with PCOS (29).

Genetic mechanisms could also play a role in the greater maternal heritability of fasting dysglycemia. The maternal parent-of-origin effects on the transmission of D19S884-A8 in dysglycemic PCOS offspring suggest gene imprinting (30). Indeed, maternal inheritance of common variants in the KCNQ1 gene in T2D in Icelandic (11) and in Pima Indian (31) cohorts suggests imprinting of diabetes susceptibility genes. Mitochondrial gene transmission, as has been found for T2D in both Japanese (32) and Caucasian populations (10), could also account for maternal heritability of dysglycemia. However, the finding of an excess maternal transmission of D19S884-A8 to dysglycemic probands should be interpreted with caution given the relatively small sample size.

Although PCOS probands were heavier, fathers and mothers had comparable ages and BMIs. The prevalence of overweight and obesity did differ in fathers and mothers, with fathers having a higher prevalence of overweight BMIs, as we have previously reported (16), and mothers having a higher prevalence of obese BMIs. Despite lower BMIs and rates of obesity than those in the PCOS probands, the metabolic profile was worse in parents, which is consistent with an important impact of age on these parameters (33). In addition, fathers had increased proinsulin to insulin molar ratios compared with mothers and probands, consistent with our previous studies suggesting that pancreatic β-cell dysfunction is a feature of the male phenotype in PCOS families (8, 34). The higher prevalence of fasting dysglycemia in fathers compared with mothers could be a consequence of this putative defect in insulin secretion. Similar sex differences in glucose homeostasis with increased prevalence rates of impaired fasting glucose in men compared with women have been reported in the general population (35).

We have previously found sex-specific metabolic abnormalities associated with D19S884-A8+: increased fasting insulin levels in women with PCOS and increased proinsulin to insulin molar ratios in their brothers (8). Such differences were absent in the current study after stratification by D19S884-A8 genotype in mothers and fathers. This discrepancy could be due to the older age of the parents as compared with the offspring, probands, and brothers (8), because age has an independent effect on insulin sensitivity and secretion (33). There was a nonsignificant trend toward increased fasting insulin levels in probands after stratification by D19S884-A8 genotype; this difference may have achieved statistical significance had the sample size been similar to our previous study (8).

In the present study, we likely substantially underestimated the prevalence of abnormal glucose tolerance because women with PCOS have primarily postprandial rather than fasting dysglycemia (36). However, fasting and postprandial glycemia are independent parameters of glucose homeostasis associated with distinct genetic loci (37). Fasting glucose levels reflect hepatic insulin sensitivity and pancreatic insulin secretion (38). Postprandial glucose levels reflect insulin-mediated glucose uptake (38). Approximately 70% of our PCOS probands were obese, consistent with the prevalence rates of obesity in U.S. cohorts of affected women (1), which would increase the prevalence of dysglycemia in these probands (36, 39). Conversely, it is possible that the prevalence of dysglycemia was decreased in the mothers receiving postmenopausal HT (40). However, this use of postmenopausal HT would have biased the findings toward the null hypothesis.

In summary, there was greater maternal heritability of fasting dysglycemia, although fathers had more adverse metabolic profiles than mothers of women with PCOS. There were maternal parent-of-origin effects on the transmission of the PCOS susceptibility allele of D19S884, D19S884-A8, to probands with fasting dysglycemia, although the relatively small sample size of families suitable for analysis could constrain the generalizability of these findings. Our study suggests that genetic mechanisms, such as gene imprinting, as well as epigenetic factors, such as the intrauterine environment, contribute to maternal heritability of fasting dysglycemia in PCOS. Because heritability analyses are population-specific (20), it is unclear whether our findings are relevant to other PCOS populations or to cohorts without PCOS.

Acknowledgments

We thank all the participants and their families for volunteering their time and effort for this study.

This work was supported by National Institutes of Health (NIH) Grants P50 HD044405 (to A.D.), R01 HD057223 (to A.D.), U54 HD034449 (to R.S.L.), and American Diabetes Association Career Development Award 7–09-CD-13 (to M.U.). P.V. was supported in part by NIH T32 DK007196. This project was also funded, in part, under a grant with the Pennsylvania Department of Health using Tobacco Settlement Funds. The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions. Some of the hormone assays were performed at the University of Virginia, Center for Research in Reproduction, Ligand Assay and Analysis Core that is supported by U54 HD028934. Partial support for some of the clinical studies was provided by M01 RR10732 and C06 RR016499 (to Pennsylvania State University General Clinical Research Center [GCRC]), M01 RR02635 (to Brigham and Women's Hospital GCRC), and UL1 RR025741 and UL1 TR000150 (to Northwestern University Clinical and Translational Sciences Institute) from the National Center for Research Resources, National Institutes of Health, which is now the National Center for Advancing Translational Sciences.

Disclosure Summary: The authors have no relevant disclosures.

Footnotes

Abbreviations:
BMI
body mass index
HT
hormone therapy
PCOS
polycystic ovary syndrome
T2D
type 2 diabetes

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