多种精神疾病可影响患者生育力

根据《美国医学会杂志-精神病学》1月刊发表的一项研究，某些精神疾病似乎与男女患者低生育率相关，提示自然选择试图阻止精神疾病患者基因变异的长久保持，从另一角度来看，新突变可能是这些疾病持续存在的原因之一(JAMA Psychiatry 2013;70:22-30)。

英国伦敦国王学院的Robert A. Power 及其同事还发现，精神疾病对男性生育力的影响大于女性。这一性别特异性影响表明，精神疾病对男性寻找合适伴侣的兴趣和能力的影响程度更大。

研究数据来自瑞典多代登记库和瑞典医院出院登记库的人口登记资料。根据患者身份号码，研究者确认了1950~1970年间出生的230余万人，这使得他们不仅能够追溯患者情况，还能够对患者兄弟姐妹的情况进行比较。截至分析时，患者年龄均大于40岁。

研究者共计追溯了大约177,000例精神分裂症、自闭症、双相障碍、抑郁症、神经性厌食症或物质滥用患者的情况，并与其261,000名兄弟姐妹以及普通人群的生育率进行了比较。

精神分裂症患者约为19,000例，他们的子女数量显著少于普通人群[男、女生育率(FR)分别为0.23和0.47]。单变量分析显示，患者姐妹的生育率明显较高(FR，1.02)。但将共病因素纳入分析后，上述差异不再存在。患者兄弟的生育率也明显较低(FR，0.97)。作者指出，上述结果表明，可能存在一种消除精神分裂症患者遗传变异的强大选择压力。这是有关新生突变对精神分裂症遗传易感性作用的又一证据，这一作用既不使精神分裂症频繁出现，又不至于使遗传变异长期存在。

自闭症患者2,947例，其兄弟姐妹4,471名。无论是男性还是女性患者，生育率均显著较低(FR分别为 0.25 和 0.48)。患者兄弟的生育率也较低(FR，0.94)，姐妹的生育率与普通人群相比未达到显著差异。自闭症患者的生育率在所有疾病患者中最低，但作者对此这并不意外，因为既往研究表明，自闭症患者几乎均不结婚或生育。他们认为，罕见的高危害性变异和性别对抗性基因多态性与孤独症遗传易感性有关。精神分裂症也与之类似，人们认为自闭症和精神分裂症是社会认知的两种极端表现。

双相障碍患者14,439例，兄弟姐妹22,986名。男性和女性患者生育率均低于普通人群(FR分别为0.75和0.85)，其兄弟生育率与普通患者相似，但姐妹生育率明显较高(FR，1.03)。但如果校正共病因素后，患者及其姐妹的生育率与普通人群的差异不再显著，患者生育率仅略低于普通人群(FR，0.94)，姐妹生育率差异也不再显著(FR，0.95)。作者称：“用于治疗双相障碍的锂盐可改善患者功能，因此，接受锂盐治疗者的生育率相对较高。”

抑郁症患者81,295例，兄弟姐妹119,645名。男性患者生育率显著低于普通人群(FR，0.93)，但女性患者生育率与普通人群无显著差异。兄弟姐妹拥有子女数量显著高于普通人群(兄弟和姐妹FR分别为1.01和1.04)。校正共病因素后，该差异未见变化。校正共病因素对男性患者生育率下降亦无影响，但可增加女性患者生育率(FR，1.03)。

研究者称，值得注意的是，抑郁症是这6种疾病中的例外。与抑郁症有关的基因似乎是通过平衡选择方式维持其存在，因为对患者的不利影响与对患者兄弟姐妹的有利影响相当。如果果真如此，这将是首个精神疾病平衡选择的有力证据。

神经性厌食症患者3,275例，兄弟姐妹5,172名。无论男性还是女性患者，其生育率均显著下降(分别为0.54 和 0.58)。患者的兄弟姐妹生育率与普通人群无显著差异。共病因素对上述结果均无影响。结果表明神经性厌食症相对于精神分裂症和自闭症而言，负性选择的作用较弱。

物质滥用患者55,933例，兄弟姐妹81,592名。男性和女性患者生育率均明显较低(FR分别为0.78 和 0.93)。兄弟姐妹子女数则明显高于普通人群(兄弟和姐妹的FR分别为1.03和1.05)。结果表明，兄弟姐妹生育率的提高几乎可完全补偿疾病对患者的影响，只是每代基因频率略微下降。考虑到从进化观点看，多数药物是一种新的环境暴露，因此对风险等位基因可能还没有足够选择时间。也有人认为，物质滥用与冒险行为相关联，包括性冒险。

该研究由英国医学研究委员会资助。作者之一报告接受了葛兰素史克(GSK)和灵北(Lundbeck)制药的咨询费和酬金。

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By: MICHELE G. SULLIVAN, Ob.Gyn. News Digital Network

Some psychiatric disorders appear to be associated with lower fecundity in both men and women, suggesting that natural selection attempts to discourage the perpetuation of genetic variants associated with them.

Instead, new mutations could be one reason that the disorders continue to exist, Robert A. Power and his colleagues wrote in the January issue of JAMA Psychiatry (formerly Archives of General Psychiatry).

The authors also found that psychiatric disorders affected men’s fecundity more than women’s. "This sex-specific effect suggests that psychiatric morbidity impairs interest or ability to find suitable mating partners or inhibits biological fertility to a greater extent in men," wrote Mr. Power of Kings College, London.

The study data were extracted from two of Sweden’s population registries – the Multi-Generation Register and the Swedish Hospital Discharge Register. More than 2.3 million people born from 1950-1970 were cross-linked by individual patient identification numbers, which allowed the researchers to trace not only patients but also their siblings. At the time of the analysis, no patient was younger than 40 years (JAMA Psychiatry 2013;70:22-30).

The authors tracked fecundity in about 177,000 patients who had schizophrenia, autism, bipolar disorder, anorexia nervosa, or substance abuse. Rates were compared with fecundity in 261,000 siblings. The researchers then compared these rates with those found in the general population.

About 19,000 patients had schizophrenia. They had significantly fewer children than the general population’s (fecundity rate [FR] 0.23 for men and 0.47 for women). In a univariate analysis, sisters of the patients had a significantly higher fecundity rate (FR, 1.02), but this difference disappeared once comorbidities were factored into the analysis. Brothers also had significantly decreased fecundity (FR, 0.97).

"Our results suggest a strong selection pressure to remove genetic variants associated with schizophrenia from the population," the authors said. "This is further evidence for the role of recent or de novo mutations in the genetic susceptibility to schizophrenia that has neither reached the frequency of nor existed long enough to be removed from the population."

Autism was present in 2,947 patients; these had 4,471 siblings. Fecundity was significantly lower in both men and women (FR, 0.25 and 0.48, respectively). Among the siblings, brothers also had fewer children (FR, 0.94). Among sisters, the rate was not significantly different than the general population.

"Individuals with autism showed the greatest reduction in fecundity among all examined disorders. This was not unexpected because previous investigations have shown that few individuals with autism ever married or had children.

"We propose that rare highly deleterious variants and sexually antagonistic polymorphisms may contribute to the genetic disposition to autism. The similarity to schizophrenia is notable because it has been proposed that the autistic and psychotic spectrums reflect two extremes of social cognition."

Bipolar disorder was present in 14,439 patients, among whom were 22,986 siblings. Fecundity was significantly lower than the general population in both men (FR, 0.75) and women (FR, 0.85). While brothers had similar rates to that of the general population, sisters had significantly more children (FR, 1.03). But incorporating comorbidities into the analysis changed the significance for both patients and sisters, with the patient rate increasing to just below that of the general population (FR, 0.94), and the sisters’ rate increased rate no longer being significant (FR, 0.95).

"It has been suggested that the introduction of lithium as a treatment for bipolar disorder has led to improved functioning and, as a result, greater fecundity in those populations where treatment is available."

There were 81,295 patients with depression, among who were 119,645 siblings. While men with depression had significantly lower rates, women with the disorder were not significantly different than the general population. Siblings had significantly more children than the general population (FR, brothers 1.01, sisters 1.04) – a difference that was unchanged by factoring in comorbidities. The addition of comorbidities to the analysis did not change the decreased ufecundity rate for male patients, but actually increased the rate for female patients (FR, 1.03).

"Notably, depression was an exception to the five other studied disorders ... genes associated with depression seems to be maintained in the population by balancing selection because the cost to affected individuals is roughly equal to the benefit to their siblings. If this is the case, it would be the first strong evidence for balancing selection in a psychiatric disorder."

There were 3,275 patients with anorexia, who had a total of 5,172 siblings. Both men and women with the disorder had significantly reduced fecundity (0.54 and 0.58, respectively). In the sibling group, there were no significant differences for either brothers or sisters. None of the findings changed when comorbidities were factored in.

"Our calculations suggest that anorexia is under weaker negative selection relative to schizophrenia and autism," the authors said.

Substance abuse was present in 55,933 patients, who had a total of 81,592 siblings. The fecundity rate was significantly lower in both men and women (FR, 0.78 and 0.93, respectively). Siblings had significantly more children than the general population (FR, 1.03 for brothers and 1.05 for sisters).

"Our findings suggest that this increased fecundity in siblings almost entirely accounts for the cost to affected individuals, with only a slight decrease in the frequency of these individuals’ genes predicted each generation. Considering that most drugs are a new environmental exposure when seen from an evolutionary perspective, it is possible that there has been insufficient time for selection to act on risk alleles. ... It has also been suggested that substance abuse is associated with risk-taking behavior in both sexes, including sexual risk taking."

The study was funded by the Medical Research Council of the United Kingdom. One of the coauthors reported having received consulting fees and honoraria from GlaxoSmithKline and Lundbeck.