> 1. I think it's genetic. Anxiety seems to run in my family. We are descended from Holocaust survivors. I think it is plausible that that one event produced strong evolutionary selection pressure in favor of paranoia and anxiety.

It's... interesting genetics.

https://www.theguardian.com/science/neurophilosophy/2011/sep...

> How might the traumatic experiences of a pregnant woman be transmitted to her unborn children? Research published over the past 10 years or so suggests that this probably occurs by epigenetic mechanisms. Epigenetics is the study of heritable changes in gene activity that are not due to changes in DNA sequence. Epigenetics reveals how genes interact with environmental factors, and has been implicated in many normal and abnormal brain functions.

> A key study in this emerging field, published in 2004, showed that the quality of a rat mother's care significantly affects how its offspring behave in adulthood. Michael Meaney of McGill University and his colleagues found that rat pups that had been repeatedly groomed and licked by their mothers during the first week of life were subsequently better at coping with stressful and fearful situations than pups who received little or no contact.

> They further showed that these effects are mediated by epigenetic mechanisms that alter expression of the glucocorticoid receptor, which plays a key role in the body's response to stress. Analysis of the pups' brains at one week old revealed differences in DNA methylation, a process by which DNA is chemically modified. Methylation involves the addition of small molecules called methyl groups, consisting of one carbon and three hydrogen atoms, to specific sites in the DNA sequence encoding a gene.

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Grandmaternal stress during pregnancy and DNA methylation of the third generation: an epigenome-wide association study - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611722/

> Stress during pregnancy may impact subsequent generations, which is demonstrated by an increased susceptibility to childhood and adulthood health problems in the children and grandchildren. Although the importance of the prenatal environment is well reported with regards to future physical and emotional outcomes, little is known about the molecular mechanisms that mediate the long-term consequences of early stress across generations. Recent studies have identified DNA methylation as a possible mediator of the impact of prenatal stress in the offspring. Whether psychosocial stress during pregnancy also affects DNA methylation of the grandchildren is still not known. In the present study we examined the multigenerational hypothesis, that is, grandmaternal exposure to psychosocial stress during pregnancy affecting DNA methylation of the grandchildren. We determined the genome-wide DNA methylation profile in 121 children (65 females and 56 males) and tested for associations with exposure to grandmaternal interpersonal violence during pregnancy. We observed methylation variations of five CpG sites significantly (FDR<0.05) associated with the grandmother’s report of exposure to violence while pregnant with the mothers of the children. The results revealed differential methylation of genes previously shown to be involved in circulatory system processes (FDR<0.05). This study provides support for DNA methylation as a biological mechanism involved in the transmission of stress across generations and motivates further investigations to examine prenatal-dependent DNA methylation as a potential biomarker for health problems.

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Intergenerational effects of maternal post-traumatic stress disorder on offspring epigenetic patterns and cortisol levels - https://www.futuremedicine.com/doi/10.2217/epi-2021-0015

> Aim: To investigate the association between maternal post-traumatic stress disorder (PTSD) during pregnancy and offspring DNA methylation and cortisol levels. Materials & methods: Blood genome-wide DNA methylation and cortisol was measured in the youngest child of 117 women who experienced sexual violence/torture during the Kosovo war. Results: Seventy-two percent of women had PTSD symptoms during pregnancy. Their children had higher cortisol levels and differential methylation at candidate genes (NR3C1, HTR3A and BNDF). No methylation differences reached epigenome-wide corrected significance levels. Conclusion: Identifying the biological processes whereby the negative effects of trauma are passed across generations and defining groups at high risk is a key step to breaking the intergenerational transmission of the effects of mental disorders

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And specifically about Holocaust survivors - Study finds epigenetic changes in children of Holocaust survivors https://www.research.va.gov/currents/1016-3.cfm

> The researchers focused on FKBP5, a stress gene linked to PTSD, depression, and mood and anxiety disorders. The results suggest that Holocaust exposure had an effect on FKBP5 methylation—a mechanism that controls the gene's expression—that was observed in parents exposed to the horrors of the concentration camps, as well as their offspring, many of whom showed signs of depression and anxiety.

> ...

> She says the researchers pursued this study because offspring of Holocaust survivors "said to us in clinic, 'we are casualties of the Holocaust and need treatment.'" Her team tested blood samples of 32 Holocaust survivors and 22 of their adult children for methylation of intron 7, an area in the FKBP5 gene. For a control group, they analyzed Jewish parents who lived outside of Europe during World War II—most were U.S.- or Canadian-born—and their offspring.

> Interestingly, Holocaust survivors and their children showed epigenetic changes at the same site of FKBP5 intron 7 but in the opposite direction. Survivors had a 10 percent higher methylation than the control parents, while the Holocaust children had a 7.7 percent lower methylation than the control children.