Table 1.

Summary of published GWAS linking single nucleotide polymorphisms within the NETRIN1/DCC signaling pathway with MDD, Depressive Symptoms or Depression-associated traits. Human genes are designated in italicized uppercase letters.

Author	Year	Total N	Cases	Controls	Replication Sample Cases	Replication Sample Control	Meta-analysis sample	Ancestry	MDD DEFINITION	GWAS hits	Putative Genes DCC or Netrin	SNP - location	Functional consequence	Notes
Okbay et al.(105)	2016	75306	16471	58835	105739			E	Frequency, in the past two-weeks, in which the respondent experienced feelings of unenthusiasm or disinterest and feelings of depression or hopelessness.	2	DCC	rs62100776	intron variant
Smith et al.(112)	2016	91370 (47196 ♀ /44174 ♂)					15346	E	Eysenck Personality Questionnaire-Revised (EPQ R-S) Short Form’s Neuroticism scale	9				Netrin-1 SNP, rs8081460, was associated with neuroticism in the UK Biobank sample. This SNP effect did not replicate in independent samples
Zeng et al.(102)	2017	6455	1123	5332	9240	9519		E	Structured Clinical Interview	1	Netrin 1			Polygenic risk scores (PRSs) calculated for netrin-1 pathway more accurately predicted MDD in one of the cohorts compared with PRS calculated for the whole genome
Dunn et al.(99)	2016	0	7179 AA, 3138 Hs					AA, Hs	Center for Epidemiological Studies of Depression Scale (CES-D)	0				The top signals in AA were rs73531535 (located 20kb from GPR139, p=5.75×10–8) and rs75407252 (intronic to CACNA2D3, p=6.99×10–7). In Hs, the top signals were rs2532087 (located 27kb from CD38, p=2.44×10–7) and rs4542757 (intronic to DCC, p=7.31×10–7).
Ward et al.(108)	2017	113968	53525	60443					Mood instability measured by a single question: ‘Does your mood often goes up and down?	4	DCC	rs8084280	intron variant
Wray et al.(107)	2018	480359	135458	344901				E	Diagnostic Interview. Cases were required to meet international consensus criteria (DSM-IV, ICD-9, or ICD-10	44	DCC	rs11663393	intron variant
Amare et al. (140)	2019	336753	90150	246603	NR	NR		E Ch ♀	Self-reported MDD (srMDD), recurrent MDD(rMDD),	1				rMDD significant SNP was not replicated in the replication sample
Howard et al. (141)	2019	807553	246363	561190	414055			E	Clinical interview and broader criteria	102	DCC	rs7227069	intron variant
Arnau-Soler et al.(109)	2019	4919 (2990 ♀ /1929 ♂)			99057			E/Sc	Questionnaire and psychological assessment	0				Post-GWAS gene-based test identified six genes assocaited with the Patient Health Questionnaire validated to screen mental illness: DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU
Barbu et al.(103)	2019	6420						E		0				PRS from the Netrin-1 signaling pathway is significantly and specifically associated with white matter integrity in thalamic radiations, namely lower fractional anisotropy, and higher mean diffusivity
Roberson-Nay et al.(114)	2018	150 pairs of MZ twins						E	DSM-V criteria for MD	0	0	0		Identified altered methylation in Netrin-1. Gene enrichment analyses implicated genes related to neuron structures and neurodevelopmental processes including cell-cell adhesion genes (e.g., CDHs, PCDHAs, PCDHA1C/2C). Genes previously implicated in mood and psychiatric disorders as well as chronic stress (e.g., HDAC4, NRG1)
Strawbridge et al.(110)	2019	122822	39265	83557	15735 & 23923	84499 & 84167		E	Questionnaire to assess suicidality phenotype	3				The gene-based analysis was used to identify genes containing potential composite association signals that were not identified by the individual SNP analysis, but which might nevertheless contribute to biological mechanisms underlying suicidality. The gene-based analysis highlighted CNTN5, ADCK3/COQ8A, CEP57, and FAM76B and DCC for suicidality. EIF4A1 and SENP3 and DCC for deliberate self-harm
Ward et al.(106)	2019	375275							Anhedonia	11	DCC	rs72923287	intron variant	PRS for anhedonia was associated with poorer brain white matter integrity, smaller total grey matter volume, and smaller volumes of brain regions linked to reward and pleasure processing, including nucleus accumbens, caudate, and medial frontal cortex. A locus in the DCC gene was the most significant hit associated with anhedonia
Lee et al.(115)	2019	727126	232964	494162				E	Cross psychiatric disorders	23 associated with at least four of the disorders	DCC	rs8084351	intron variant	The region surrounding SNP rs8084351 at the gene DCC featured the most pleiotropic association. This region showed association with all eight psychiatric dissordes studied (MD, SCZ, BIP, ADHD, ASD, TS, ANO, OCD)

E=european

Sc=Scottish

rMDD=recurrent major depression

ASD=Autism spectrum disorder

AA= African American

BIP=Bipolar Disorder

MD= Major Depression

TS=tourette syndrome

Hs: Hispanic

TS= two samples

SCZ= Schizophrenia

ANO=anorexia nervosa

Ch= Chinese

PRS=Poygenetic Risk Score

ADHD= Attention deficit hyperactivity disorder

OCD=Obsessive–compulsive disorder