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Family-based quantitative trait meta-analysis implicates rare noncoding 1 variants in DENND1A in pathogenesis of polycystic ovary syndrome 2 3 4 ABSTRACT 33Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders of 34 premenopausal women, affecting 5-15% of this population depending on the diagnostic 35 criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction and 36 polycystic ovarian morphology. PCOS is a leading risk factor for type 2 diabetes in young 37 women. PCOS is highly heritable, but only a small proportion of this heritability can be 38 accounted for by the common genetic susceptibility variants identified to date. To test the 39 hypothesis that rare genetic variants contribute to PCOS pathogenesis, we performed 40 whole-genome sequencing on DNA from 62 families with one or more daughters with PCOS. 41We tested for associations of rare variants with PCOS and its concomitant hormonal traits 42 using a quantitative trait meta-analysis. We found rare variants in DENND1A (P=5.31×10 -5 , 43Padj=0.019) that were significantly associated with reproductive and metabolic traits in 44 PCOS families. Common variants in DENND1A have previously been associated with PCOS 45 diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A 46 is an important regulator of human ovarian androgen biosynthesis. Our findings provide 47 additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding 48 variants contribute to disease pathogenesis. 50Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5-15% of 52 premenopausal women worldwide 1 , depending on the diagnostic criteria applied. PCOS is 53 diagnosed by two or more of its reproductive features of hyperandrogenism, ovulatory 54 dysfunction, and polycystic ovarian morphology. It is frequently associated with insulin 55 resistance and pancreatic β-cell dysfunction, making it a leading risk factor for type 2 diabetes 56 in young women 2 . 57PCOS is a highly heritable complex genetic disorder. Analogous to other complex traits 3 , 58 common susceptibility loci identified in genome-wide association studies (GWAS) 4-8 account 59 for only a small proportion of the estimated genetic heritability of PCOS 9 . As GWAS were 60 designed to assess common allelic variants, usually with minor allele frequencies (MAF) ≥2-61 5%, it has been proposed that less frequently occurring variants with greater effect sizes 2 account for the observed deficit in heritability 10 . Next generation sequencing approaches have 63 identified rare variants that contribute to complex disease pathogenesis [11][12][13][14][15][16] . 64We tested the hypothesis that rare variants contribute to PCOS by conducting family-based 65 association analyses using whole-genome sequencing data. We filtered and weighted rare 66 variants (MAF ≤2%) according to their predicted levels of deleteriousness and grouped them 67 regionally and by genes. We not only tested for associations with PCOS diagnosi...

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