Genome Wide Association Studies On PCO –What does such studies tell us on candidate genes related to insulin signaling,

 

The  first   GWAS  in PCOS   was performed by a  group based  at Shandong   University    in china.  The discovery  set included 744 PCOS   cases and 895   controls and   subsequent   replications  involved   tow independent   large cohorts  of Han Chinese    women with PCOS  and controls. Three   genome wide significant   loci were   identified   showing strong   associations with PCOS  located    at chromosome  2  and chromosome 9   . In a second   GWAS  published one year   later  they identified  9 new loci that  significantly   associated  with PCOS. The  PCOS  associated   signals   showed evidence   of enrichment for candidate   genes related to insulin signaling gonadotropic   hormone function   and type  2 diabetes. Other   candidate   genes were related   to calcium  signaling   and endocytosis.

A  few  years later   a study  in American   women from  European   descent was published identifying two   new loci   reach   mapping to chromosome    8 and  chromosome   11 and a  known  locus  on chromosome  9  previously found in Chinese  GWAS. The  SNP  on chromosome 11 in the region of the   follicle   stimulating hormone  B   polypeptide     gene   was strongly  associated   with  the former PCOS   NIH   diagnosis   as well as  with  luteinizing   hormone  levels. In the  same   year a large  European   collaboration   produced  another  GWAS   on PCOS. Six  signals   for PCOS  in or near known   genes were identified   . Mendelian randomization  analyses   indicate   causal roles  in PCOS etiology  for higher  BMI, higher  insulin  resistance   and lower serum sex hormone   binding globulin  concentrations . Furthermore, genetic   susceptibility   to later menopause  is significantly associated with   higher   PCOS risk   and PCOS. Susceptibility  alleles  are significantly associated   with higher serum anti Mullerian hormone   concentration  in girls.

Another   GWAS   in Korean women consisted  of 976   PCOS   cases and   946  controls   with a replication   cohort   including    249 PCOS   cases and  778   controls . One   novel   locus   with genome   wide significance   and seven    moderately   associated   loci for PCOS   were identified.   The strongest association    was on   chromosome 8  .

The latter   signal  was located  upstream  of the KHDRBS3  gene, which    is associated    with telomerase   activity  and could drive  PCOS   and related   phenotypes.

Another   GWAS  compared   patients  with PCOS  with   women   from infertile couples  due to tubal   occlusion or male factor    infertility genes   identified  were the  known THADA, DENND 1A   and a new   locus in the TOX3  gene.

A recent   meta analysis   cross ethnic effects  of the  through    GWAS    identified  genetic   variants   showed  that  overall  for 12 of 17  genetic variants   mapping to the  Chinese   PCOS   loci similar effect sizes  and identical   directions in PCOS    patients   from Northern European   ancestry indicating   a common genetic   risk profile   for PCOS across   populations. Therefore   it is    expected   that large   GWAS  in PCOS   patients   from Northern European   ancestry will partly identify similar   loci as the GWAS   in Chinese   PCOS   patients.

Indeed   in the most   recent   study  in over 10,000 cases   of PCOS and over  100,000   controls of  European  ancestry   identified   only 3 novel    loci  and replicated   11   previously     reported loci    . Strikingly  this study    showed that the genetic   architecture   was similar     between PCOS   diagnosed by  self report   and PCOS  diagnosed by NIH  or non  NIH   . Rotterdam  criteria   across common   variants   at 13 loci. Identified  variants  were associated   with hyperandrogenism ,  gonadotropin   regulation and testosterone   levels in affected women. Moreover linkage   disequilibrium  score regression analysis   revealed   genetic  correlations with   obesity , fasting insulin type 2  diabetes , lipid  levels   and coronary  artery disease, indicating   shared genetic architecture between  metabolic    traits   and PCOS. Finally   , Mendelian randomization analysis    indicate    causal   roles in PCOS   etiology  for higher DMI, higher    insulin   resistance   and lower   serum sex hormone   binding  globulin concentrations. Furthermore     genetic susceptibility   to later   menopause  is significantly associated with higher  PCOS risk and  PCOS  susceptibility alleles are significantly associated    with higher  serum   anti Mullerian  hormone   concentration  in girls.

Another GWAS  in Korean   women consisted of 976   PCOS cases in 946   controls   with a replication cohort   including   249 PCOS   cases  and 778   controls . One  novel locus   with genome   identified    were the  known   THADA, DENND1A  and a new   locus  in the TOX3 gene .

A recent   meta analysis  cross ethnic   effects  of the through GWAS   identified genetic    variants  showed   that overall  for 12 of 17   gene   variants    mapping   to the Chinese PCOS  loci similar  effect sizes and   identical directions   in PCOS  patients from  Northern European   ancestry indicating   a common genetic  risk profile   for PCOS   across populations . Polycystic ovary  syndrome   is the  most common   endocrine   disorder  in women   characterized  by ovulatory   dysfunction , hyperandrogenism, and  polycystic   ovarian   morphology   . The   diagnosis   is made according   to the so called  2003   Rotterdam   consensus criteria   . The prevalence varies   between  5 and 20 5  depending  on  which    population is assessed. The incidence    is generally lower in unselected population   based samples   compared  to hospital  referred  patients.