The thoughts and behaviors preceding death by suicide can be modeled by a severity spectrum termed ‘suicidality.’ Twin, family, and adoption studies recognize a heritability of suicide ideation, suicidal behaviors, and suicidality in the range of 30-50%. A large genome-wide gene-by-environment interaction study of >120,000 participants of European descent identified Contactin-5 (CNTN5) as a risk conferring locus for suicidality. Suicidality genetic architecture overlaps with suicidal thoughts (99%), attempt (68%), major depressive disorder (81%), and posttraumatic stress disorder (42%). However, the shared biology between suicidality, suicide outcomes, and comorbidities is unclear. Furthermore, it is uncertain how contactin-5 and other members of the contactin family independently and collectively contribute to suicide outcome risk. We hypothesize that characterizing genetic heterogeneity will reveal novel biological insights for suicide outcomes. We address genetic heterogeneity with two aims focused on different types of genetic variation. First, using cross-ancestry and ordinal-trait-aware genome-wide association methods in approximately 156,000 participants, we will uncover risk loci for suicidality and suicide outcomes in underrepresented minority populations to close a critical gap in suicide epidemiology. Using our recently developed analytic pipeline to re-test suicide genetic associations given comorbid conditions, we will uncover suicide specific risk loci, tissue and cell-type transcriptomic information, 3-dimensional regulatory elements, and cross-trait genetic correlative and causal relationships (mentored by Dr. Ronald Kessler). The second aim of this proposal deeply characterizes the risks conferred by the contactin gene family implicated in suicidality (and in studies of schizophrenia, autism spectrum disorder, and Tourette syndrome). Contactins may confer conditionally independent risks on psychopathology due to their differential involvement in neurite branching (contactin 5) and neurite elongation (contactins 4 and 6). From whole exome sequences, we will investigate the effects of rare variant in contactins using an analysis based on individual and combined variant effects. We will evaluate the relevance of traumatic experiences rare contactin variant effects, a result our group detected previously using common variants. The implications of these data are two-fold. First, this study is suitably powered to uncover risk loci for suicide outcomes in minority populations who, though at highest risk for suicide, are often excluded from genetic studies. Our use of novel ordinal-trait aware regression statistics improve power over conventional genome-wide models. Second, we propose a novel approach to studying a small family of genes routinely implicated in suicide biology that may reveal how suicidality is connected to its related psychopathologies thereby informing potential treatment strategies. I expect to uncover novel risk loci and relevant biology with which to inform treatment and intervention strategies in high risk populations. Though this proposal stems from the hypothesis that genetic heterogeneity informs suicide biology, it is designed in a data-driven manner to generate long-term hypotheses with which my independent research group will investigate deeper from future funding applications. The breadth of analysis proposed herein are expected to serve as preliminary data for the development of AFSP Standard Research Innovation Grant and Focus Grant mechanisms.
