Effects of prenatal exposure to the 1944–45 Dutch famine and glucocorticoid receptor polymorphisms on later life PTSD susceptibility

Figures & data

Table 1. Characteristics of participant groups according to timing of exposure to prenatal famine.

	Control		Prenatal famine exposure			p-value
	Born before famine (n = 139)	Conceived after famine (n = 125)	Late gestation (n = 75)	Mid gestation (n = 67)	Early gestation (n = 33)
Age (years)	73.3 (1.0)	71.5 (0.5)	72.8 (0.4)	72.0 (0.2)	72.0 (0.0)
PCL5^a total score	10.5 (10.9)	10.9 (11.3)	8.3 (9.9)	11.2 (11.2)	12.9 (12.9)	.397
Probable PTSD based on PCL5^a total score	6 (4.3%)	9 (7.2%)	2 (2.7%)	2 (3.0%)	3 (9.1%)	.424
LEC^b total score	1.04 (1.33)	0.92 (1.17)	1.24 (1.53)	1.27 (1.26)	1.27 (1.28)	.223
CTQ^c total score	36.8 (10.6)	37.5 (15.5)	36.9 (11.3)	37.8 (12.4)	39.1 (14.8)	.929
CTQ MD^d score	0.76 (1.04)	0.71 (0.98)	0.72 (1.05)	0.49 (0.93)	0.61 (0.90)	.166
Education level	4.8 (1.4)	4.7 (1.5)	4.9 (1.5)	4.8 (1.2)	4.9 (1.1)	.743
Sex						.185
Women	73 (52.5%)	65 (52.0%)	37 (49.3%)	44 (65.7%)	19 (57.6%)
Men	66 (47.5%)	60 (48.0%)	38 (50.7%)	23 (34.3%)	14 (42.4%)
Marital status^e						.732
Long-term relationship	87 (62.6%)	92 (73.6%)	49 (66.2%)	46 (68.7%)	25 (75.8%)
Single	23 (16.5%)	15 (12.0%)	14 (18.9%)	8 (11.9%)	2 (6.1%)
Widower	28 (20.1%)	16 (12.8%)	11 (14.9%)	13 (19.4%)	6 (18.2%)

Data are displayed as means (SD) for continuous variables and frequencies (%) for categorical variables.

^a PTSD checklist for the DSM-5

^b Life events checklist for the DSM-5

^c Childhood trauma questionnaire

^d Minimization denial score of childhood trauma questionnaire

^e Missing data for n = 4 participants (n = 3 controls, n = 1 late gestation)

Figure 1. Overview of the five identified glucocorticoid receptor haplotypes based on the four investigated common single nucleotide polymorphisms (SNPs) within this gene, and their respective frequencies within the cohort (based on two estimated haplotypes per participant).

Table 2. Frequencies of haplotype carriers within participant groups according to occurrence and timing of exposure to prenatal famine and according to probable PTSD diagnostic status.

	Most common haplotype	BclI SNP haplotype	Exon 9B haplotype	N363S haplotype	ER22/23K + exon 9β haplotype	p-value
Prenatal famine exposure						.873
Controls	179 (59.7)	163 (61.5)	70 (60.3)	18 (54.5)	14 (53.8)	445
Late exposure	51 (17.0)	45 (17.0)	19 (16,4)	6 (18.2)	3 (11.5)
Mid exposure	45 (15.0)	38 (14.3)	20 (17.2)	5 (15.2)	8 (30.8)
Early exposure	25 (8.3)	19 (7.2)	7 (6.0)	4 (12.1)	1 (3.8)
Probable PTSD based on PCL5^a total score						.942
Yes	15 (5.0)	12 (4.5)	7 (6.0)	2 (6.1)	1 (3.8)
No	285 (95.0)	253 (95.5)	109 (94.0)	31 (93.9)	25 (96.2)

Data are displayed as absolute (n) and relative (%) frequency of haplotype carriers (either homozygous with two copies per haplotype pair or heterozygous with one copy per haplotype pair).

^a PTSD checklist for the DSM-5

Table 3. Results of linear regression analyses including the effects of GR haplotype carrier status, prenatal famine exposure and childhood trauma on PTSD symptom severity in late adulthood, with separate models for the most common haplotype, the BclI haplotype and the Exon 9β haplotype.

	Most common haplotype			BclI SNP haplotype			Exon 9β haplotype
Predictors	B	SE	BCA CI (97.5%)	B	SE	BCA CI (97.5%)	B	SE	BCA CI (97.5%)
Intercept	−0.65	1.41	−3.81–2.51	−2.27	1.16	−4.87–0.33	−2.32	0.90	−4.35 to −0.29
CTQ total score^a	0.70	0.39	−0.18–1.57	1.21	0.32	0.49–1.93	1.18	0.25	0.62–1.73
Marital status (single)^b	0.21	0.13	−0.10–0.51	0.18	0.13	−0.11–0.48	0.20	0.13	−0.10–0.50
Marital status (widower)^b	0.19	0.13	−0.10–0.48	0.20	0.13	−0.09–0.49	0.20	0.13	−0.09–0.49
Sex (female)^b	0.14	0.09	−0.08–0.35	0.15	0.09	−0.06–0.36	0.17	0.09	−0.04–0.38
CTQ MD score^c	−0.07	0.05	−0.19–0.05	−0.08	0.05	−0.20–0.04	−0.08	0.05	−0.20–0.04
Late exposure^b	0.80	2.72	−5.33–6.92	−0.23	2.61	−6.11–5.65	3.24	1.91	−1.06–7.54
Mid exposure^b	−1.46	2.79	−7.75–4.82	0.23	2.41	−5.20–5.65	2.62	1.91	−1.68–6.92
Early exposure^b	1.84	5.13	−9.71–13.39	−3.66	3.22	−10.90–3.57	−1.05	2.07	−5.71–3.60
Haplotype carrier status (≥1 copies)^d	−1.88	1.59	−5.47–1.70	0.49	1.43	−2.72–3.70	1.47	1.65	−2.24–5.18
CTQ*Late exposure	−0.20	0.75	−1.89–1.48	−0.01	0.72	−1.62–1.60	−0.97	0.53	−2.17–0.22
CTQ*Mid exposure	0.39	0.77	−1.33–2.11	−0.08	0.67	−1.58–1.42	−0.76	0.53	−1.95–0.44
CTQ*Early exposure	−0.44	1.44	−3.68–2.80	1.04	0.89	−0.96–3.03	0.26	0.57	−1.01–1.54
Late exposure*Haplotype	3.28	3.39	−4.35–10.90	5.26	3.33	−2.23–12.75	−0.71	3.59	−8.79–7.38
Mid exposure*Haplotype	3.09	3.41	−4.59–10.77	0.83	3.19	−6.33–8.00	−5.72	3.48	−13.55–2.12
Early exposure*Haplotype	−2.71	5.54	−15.19–9.76	4.39	4.01	−4.63–13.41	3.39	5.74	−9.53–16.31
CTQ* Haplotype	0.56	0.44	−0.43–1.55	−0.19	0.40	−1.08–0.70	−0.38	0.46	−1.41–0.66
CTQ*Late exposure*Haplotype	−1.01	0.94	−3.12–1.09	−1.43	0.92	−3.50–0.63	0.29	0.99	−1.94–2.53
CTQ*Mid exposure*Haplotype	−0.87	0.94	−2.98–1.25	−0.24	0.88	−2.22–1.74	1.59	0.95	−0.55–3.74
CTQ*Early exposure* Haplotype	0.66	1.55	−2.82–4.14	−1.24	1.10	−3.72–1.24	−0.76	1.58	−4.32–2.81
N included	428			428			428
R^2 / R^2 adjusted	0.160 / 0.121			0.173 / 0.135			0.173 / 0.135

^a Childhood trauma questionnaire (log-transformed)

^b Long-term relationship used as the reference group for marital status; men used as the reference group for sex; non-exposed control group used as the reference group for prenatal famine exposure

^c Minimization denial score of childhood trauma questionnaire

^d 1 or 2 copies of haplotype carried compared to no copies carried as a reference

Log transformed PCL-5 scores as the outcome variable

BCA CI = bias corrected and accelerated confidence intervals

Figure 2. Visualisation of PTSD symptom severity scores as a function of BclI haplotype carrier status, prenatal famine exposure and adulthood trauma. The association between the number of trauma types experienced during adulthood (LEC total score) and PTSD symptom severity (log-transformed PCL-5 total scores) is depicted for each prenatal exposure group and controls separately, divided into non-carriers (left panel) and BclI haplotype carriers (homozygous or heterozygous, right panel).

Table 4. Results of linear regression analyses including the effects of GR haplotype carrier status, prenatal famine exposure and adulthood trauma on PTSD symptom severity in late adulthood, with separate models for the most common haplotype, the BclI haplotype and the Exon 9β haplotype.

	Most common haplotype			BclI haplotype			Exon 9β haplotype
Predictors	B	SE	BCA CI (97.5%)	B	SE	BCA CI (97.5%)	B	SE	BCA CI (97.5%)
Intercept	1.58	0.14	1.26–1.92	1.82	0.12	1.52–2.10	1.67	0.10	1.44–1.90
LEC total^a	0.22	0.08	0.02–0.44	0.16	0.07	0.01–0.30	0.19	0.06	0.06–0.33
Marital status (single)^b	0.41	0.13	0.10–0.71	0.45	0.13	0.15–0.73	0.4	0.13	0.10–0.70
Marital status (widower)^b	0.13	0.13	−0.14–0.41	0.16	0.13	−0.12–0.46	0.17	0.13	−0.13–0.47
Sex (female)^b	0.13	0.10	−0.07–0.26	0.13	0.10	−0.08–0.34	0.13	0.10	−0.09–0.34
Late exposure^b	0.12	0.30	−0.75–0.75	−0.17	0.26	−0.73–0.38	−0.20	0.18	−0.61–0.20
Mid exposure^b	−0.01	0.28	−0.75–0.74	−0.07	0.28	−0.69–0.54	−0.29	0.21	−0.77–0.18
Early exposure^b	0.32	0.46	−1.81–1.70	−0.99	0.42	−2.02–0.18	−0.16	0.27	−0.78–0.46
Haplotype carrier status (≥1 copy)^c	0.14	0.16	−0.24–0.54	−0.23	0.15	−0.59–0.14	0.07	0.17	−0.32–0.45
LEC*Late exposure	−0.11	0.20	−0.53–0.38	−0.06	0.12	−0.33–0.21	−0.05	0.10	−0.28–0.17
LEC*Mid exposure	−0.03	0.13	−0.37–0.58	0.09	0.18	−0.31–0.49	0.13	0.12	−0.13–0.39
LEC*Early exposure	−0.00	0.41	−1.49–1.44	0.58	0.20	0.17–1.01	0.08	0.16	−0.28–0.45
Late exposure*Haplotype	−0.33	0.35	−1.06–0.55	0.19	0.33	−0.53–0.89	0.4	0.42	−0.55–1.34
Mid exposure*Haplotype	−0.42	0.36	−1.35–0.55	−0.24	0.36	−1.04–0.90	0.22	0.38	−0.62–1.07
Early exposure*Haplotype	−0.55	0.55	−2.27–1.66	1.48	0.51	0.05–2.72	0.52	0.59	−0.81–1.85
LEC*Haplotype	−0.03	0.10	−0.27–0.20	0.07	0.1	−0.16–0.30	0.03	0.10	−0.19–0.26
LEC*Late exposure*Haplotype	0.03	0.22	−0.50–0.51	−0.07	0.17	−0.48–0.36	−0.17	0.21	−0.66–0.31
LEC*Mid exposure*Haplotype	0.32	0.19	−0.33–0.80	−0.03	0.21	−0.65–0.56	−0.12	0.19	−0.55–0.31
LEC*Early exposure*Haplotype	0.14	0.43	−1.43–1.67	−1.01	0.28	−1.77 to −0.18	−0.01	0.31	−0.71–0.69
N included	430			430			430
R^2 / R^2 adjusted	0.137 / 0.099			0.162 / 0.125^d			0.141 / 0.103

^a Life events checklist for the DSM-5

^b Long-term relationship used as the reference group for marital status; men used as the reference group for sex; non-exposed control group used as the reference group for prenatal famine exposure.

^c 1 or 2 copies of haplotype carried compared to no copies carried as a reference

Log transformed PCL-5 scores as the outcome variable

^d The model as a whole was significant (F(18, 403) = 4.23, p = 2.86e-08)

BCA CI = bias corrected and accelerated confidence intervals

Data availability statement

The data that support the findings of this study are available on request from the corresponding author, MVZ. The data are not publicly available as they contain information that could compromise participant privacy.