Professor, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo
Dr. Rebar reports no financial relationships relevant to this field of study.
SYNOPSIS: Rare noncoding variants of the gene DENND1A, previously shown to play a key role in androgen biosynthesis in human ovarian theca cells, are significantly associated with familial polycystic ovary syndrome.
SOURCE: Dapas M, Sisk R, Legro RS, et al. Family-based quantitative trait meta-analysis implicates rare noncoding variants in DENND1A in polycystic ovary syndrome. J Clin Endocrinol Metab 2019; Apr 30. doi:10.1210/jc.2018-02496.
Although polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, and clearly often has a familial distribution, its etiology remains unknown. Even though it remains variably defined, clinicians and investigators agree that the most severe phenotypes of PCOS are present in affected individuals who meet the NIH criteria for PCOS, which consist of clinical or biochemical evidence of hyperandrogenism and evidence of anovulation in the absence of other significant endocrine disturbances.1 Previous genome-wide association studies (GWAS), which examined common allelic variants, can account for only a small proportion of the estimated genetic heritability of PCOS.2-6
It has been suggested that rare variants with greater effect sizes might play a larger role in highly complex genetic disorders.7 Dapas et al tested the hypothesis that rare variants contribute to the heritability of PCOS by examining family-based association analyses of the entire genome. In this complex genetic study, investigators performed whole-genome sequencing on DNA obtained from 261 individuals from 62 families with one or more daughters with PCOS as based on the NIH definition of the syndrome. They found 32 variants (two coding, 30 noncoding) in the DENND1A gene that were significantly associated with reproductive and metabolic traits in families with members with PCOS (adjusted P = 0.039).
Women with one or more of these DENND1A variants had significantly higher ratios of luteinizing hormone (LH) to follicle-stimulating hormone (FSH), common in individuals with PCOS, than those without any of these variants. Unaffected women with one or more of these variants also tended toward higher LH-to-FSH ratios than unaffected women without variants (P = 0.1758). Fifty percent of the families with members with PCOS carried at least one of the rare DENND1A variants. Typically, each individual variant was present in one or two families, suggesting that causal variants are individually uncommon but collectively may occur in key genes regulating, in this case, androgen biosynthesis. No other set of rare variants reached significance for association with quantitative trait levels for PCOS.
Why did I choose to summarize an article that virtually no obstetrician-gynecologist would choose to read on their own? For two reasons: First, because we are learning that genetic mutations affect many diseases, including PCOS, and that this is true even for those disorders that are not classically genetic in origin. Second, it gives me the opportunity to briefly discuss the etiology of PCOS.
This study identified rare variants in DENND1A that were significantly associated with altered reproductive and metabolic hormone levels in PCOS. In a GWAS study of Han Chinese women, common variants of DENND1A were associated with PCOS,2 and these associations were replicated in women of European ancestry.8 Thus, this study supports a causal role for variants of DENND1A in at least some women with PCOS.
DENND1A encodes a connecdenn protein that plays a role in internalization of proteins and lipids. As has been learned about most genes, their actions frequently are diverse and more complicated than what the name of the gene might suggest. Thus, DENND1A has been shown to play a key role in androgen biosynthesis in human theca cells and is upregulated in theca cells from women with PCOS.9,10
Several other GWAS candidate genes from other GWAS studies examining common allelic variants for PCOS appeared among the top gene associations in the study by Dapas et al, but they failed to reach significance. These includedC9orf33,4,6 (encoding an M1 metalloproteinase), HMG23 (encoding a high-mobility group AT-hook 2 protein expressed during early development), ZBTB166 (a zinc finger protein coding gene associated with genital hypoplasia among other things), TOX33,6 (encoding a high mobility group box family member 3, which functions to modify chromatin structure), and THADA2,3,5,6 (encoding a thyroid adenoma-associated protein). In addition, two other plausible candidate genes showed strong, but not genome-wide-significant, associations with PCOS traits in this study. These genes are BMP6, which is expressed in granulosa cells and has been found to be higher in those granulosa cells from women with PCOS compared to cells from normal women,11 and PRDM2, which is an estrogen receptor coactivator that is highly expressed in the ovary and pituitary gland.12
As postulated by the authors, the results of this study align with emerging evidence that rare coding variants with large effect sizes do not play a major role in complex disease.13 Rather, they suggest that complex traits may be driven primarily by noncoding variation. I am not surprised by the conclusion that variants in a single gene do not play the only role in the etiology of PCOS. Nor am I surprised by the data that common susceptibility loci identified in earlier GWAS studies account for little of the estimated genetic heritability of PCOS.2-6 Let us not forget that PCOS is a syndrome and not a well-defined disease. Even the definition has been the subject of significant debate. Remember that increased androgens from any source can result in polycystic-appearing ovaries.14
Thus, polycystic-appearing ovaries are present in Cushing syndrome and in androgen-producing tumors of the ovary or adrenal gland. While Cushing syndrome and androgen-secreting tumors must be excluded before a diagnosis of PCOS is established, such is not the case for women who gain significant weight and develop the manifestations of PCOS. Obesity, which eventually alters the ratio of estrogen to androgen in virtually all women, commonly results in PCOS. Polycystic ovaries also arise in laboratory mammals experimentally provided with excess quantities of androgens. Thus, the development of polycystic ovaries, including other manifestations of the syndrome, is one of the ways in which the ovaries can respond to a variety of endocrine disturbances. We also know that insulin resistance and pancreatic β-cell dysfunction are common in the disorder and can envision (genetic) etiologies arising primarily from these metabolic disturbances.
Why should we suspect that the etiology will be confined neatly to a variant or variants in a single, or even a few, genes? It certainly is true that we are learning that gene variants increase susceptibility to disease and play an important role in many, if not most, diseases. For this reason, it is important for clinicians to monitor advances in molecular genetics. Clearly, gene variants are expected to influence “personalized” medical therapy in the future. This may well be true even of a complex disorder such as PCOS. We may tailor treatment based on the pathophysiologic basis of PCOS once we have the capability to identify the etiology in individual patients. This study offers evidence of an advance in our ability to determine etiology.
- Zawadski J, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: Towards a rational approach. In: Dunaif A, Givens J, Haseltine F, Merriam G, eds. Polycystic Ovary Syndrome. Boston: Blackwell Scientific; 1992:377-382.
- Chen ZJ, Zhao H, He L, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet 2011;43:55-59.
- Shi Y, Zhao H, Shi Y, et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet 2012;44:1020-1025.
- Hayes MG, Urbanek M, Ehrmann DA, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun 2015;6:7502.
- Day FR, Hinds DA, Tung JY, et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun 2015;6:8464.
- Day F, Karaderi T, Jones MR, et al. Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnostic criteria. PLoS Genet 2018;14:e1007813.
- Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature 2009;461:747-753.
- Welt CK, Styrkarsdottir U, Ehrmann DA, et al. Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. J Clin Endocrinol Metab 2012;97:E1342-E1347.
- McAllister JM, Modi B, Miller BA, et al. Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proc Natl Acad Sci U S A 2014;111:E1519-E1527.
- Tee MK, Speek M, Legeza B, et al. Alternative splicing of DENND1A, a PCOS candidate gene, generates variant 2. Mol Cell Endocrinol 2016;434:25-35.
- Khalaf M, Morera J, Bourret A, et al. BMP system expression in GCs from polycystic ovary syndrome women and the in vitro effects of BMP4, BMP6, and BMP7 on GC steroidogenesis. Eur J Endocrinol 2013;168:437-444.
- Di Zazzo E, De Rosa C, Abbondanza C, Moncharmont B. PRDM proteins: Molecular mechanisms in signal transduction and transcriptional regulation. Biology (Basel) 2013;2:107-141.
- Wray NR, Wijmenga C, Sullivan PF, et al. Common disease is more complex than implied by the core gene omnigenic model. Cell 2018;173:1573-1580.
- Yen SS. The polycystic ovary syndrome. Clin Endocrinol (Oxf) 1980;12:177-207.