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Gene x Ovarian Hormone Interactions in Perimenopausal Risk for Psychosis

Award Number: R01MH140527
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/08/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Gene x Ovarian Hormone Interactions in Perimenopausal Risk for Psychosis - PROJECT SUMMARY Women show a heightened risk for psychosis in midlife that is not observed in men. In our ongoing R01 project, we have shown that perimenopausal changes in ovarian hormones (estrogen, progesterone) contribute to the midlife increase in psychosis risk. These findings substantially increase our understanding of midlife psychosis risk in women. However, the picture is critically incomplete. Not every woman develops psychosis during the hormonal changes of perimenopause. Only a subset of women develops these debilitating symptoms, and a crucial next step in this high-priority area of women’s health is to determine why some women are more prone to psychosis during perimenopause. In this application, we propose that differences in genetic vulnerability substantially increase perimenopausal risk of psychosis in some women. The Specific Aims are to identify these gene x menopausal stage interactions to identify for whom perimenopause is risky (Aim 1) and elucidate gene x ovarian hormone interactions to explain why they are at increased risk (Aim 2). We will address these aims by expanding our ongoing R01 that collects daily psychotic symptoms and daily ovarian hormone levels across 35 consecutive days in a population-based sample of women who vary in menopausal status (i.e., premenopause, perimenopause, postmenopause) and are enriched for psychosis. The proposed project will increase the sample of women (N = 250 additional women; total N = 1000 women), collect DNA samples, and use them to construct both global and pathway-specific polygenic risk scores (PRSs/pPRSs) for disorders associated with psychosis vulnerability (e.g., schizophrenia, bipolar disorder) and key neurobiological circuits (e.g., dopaminergic, glutamatergic) implicated in psychosis. Using these novel PRSs/pPRSs, together with daily symptom data, we will show that women who are at greater genetic risk and in perimenopause exhibit significantly more psychotic symptoms in midlife (Aim 1). We will further extend these mechanistic insights by using daily saliva samples of ovarian hormones to confirm that women who are at greater genetic risk will show the most profound increases in daily psychotic symptoms in response to changing estrogen and progesterone levels during perimenopause (Aim 2). Our project’s combination of novel genomic data with daily symptom and hormone measures is highly unique and will allow us to answer critical questions about for whom perimenopause is risky and why. Our application directly addresses the PAR high priority area “Research clarifying the mechanistic role of reproductive steroids in generating, moderating, or mitigating mood and psychosis symptoms during the menopausal transition.” Elucidating critical hormonal and genetic mechanisms underlying individual differences in perimenopausal risk can advance etiologic models of midlife psychosis, guide women’s health policy, and inform personalized medicine approaches to prevention and intervention (NIMH Strategic Plan Goal 3).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $796,106 )
2026	2026	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 360	EAST LANSING	MI	48824	INGHAM	USA	Mental Health Research Grants	000	1	9/10/2026	NEW	$796,106
														Subtotal = $796,106

Grand Total All Awards = $796,106

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Gene x Ovarian Hormone Interactions in Perimenopausal Risk for Psychosis

Award Number: R01MH140527

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/08/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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