Familial clustering of suicide and major depressive disorder: an observational analysis

[摘要] Depression is considered the third most important burden of disease globally; further, it is ranked first in middle and high-income countries. It is well understood that depression is has a heritability of 31-43%, but no genetic associations predisposing individuals to depression have been found. A small group of individuals have previously been identified with treatment resistant major depressive disorder (TR-MDD), suicidality and a myriad of metabolic alterations. This is considered a neuropsychiatric inborn error of metabolism that initially presents with psychiatric manifestation. The most common metabolic finding is cerebral folate deficiency. Supplementation of folinic acid has been shown to result in a reduction of symptoms. Understanding this group of individuals, particularly with the knowledge that metabolic disease commonly manifests with psychiatric illness, has implications for the way depression may be diagnosed and treated in the future. This study captured and analyzed the family histories of 36 individuals in an attempt to discern whether the transmission of depression and suicide in these families fits known Mendelian inheritance patterns. By using segregation analysis in addition to an observational analysis this study has assessed autosomal recessive and autosomal dominant inheritance patterns. Observation of family histories showed male-to-male transmission and thus excluded the possibility of X-linked or mitochondrial inheritance in this group. The observational study identified that 6/36 families (16.7%) met all criteria for autosomal dominant inheritance and no families met all criteria for autosomal recessive inheritance. The just over 30% of families met a few, but not all of the criteria for autosomal dominant inheritance (11/36) and 33 of 36 families or 91.67% met only one criterion for autosomal recessive inheritance. This suggests that these families are transmitting depression and suicidality in a polygenic or multifactorial pattern. The statistical analysis supports this conclusion finding that the families fit a non-Mendelian pattern of inheritance. Understanding the way depression is being transmitted in these families has significant public health relevance as it may inform our understanding and future studies of the genetics of depression, a significant health burden.

[发布机构] the University of Pittsburgh